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Enomoto Y, Shiromizu T, Yasojima S, Koiwa J, Kuroda Y, Ito H, Yuge M, Ohkawa M, Shibata R, Murakami H, Naruto T, Shiiya S, Omotani N, Nishimura Y, Kurosawa K. Two distinct phenotypes in Snijders Blok-Campeau syndrome and characterization of the behavioral phenotype in a zebrafish model. Eur J Hum Genet 2025:10.1038/s41431-025-01815-y. [PMID: 39988727 DOI: 10.1038/s41431-025-01815-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 01/28/2025] [Accepted: 02/10/2025] [Indexed: 02/25/2025] Open
Abstract
Chromatin remodeling is an important system controlling gene expression. CHD3, which is a causative gene of Snijders Blok-Campeau syndrome (SNIBCPS), is a member of the chromodomain helicase DNA-binding (CHD) family related to chromatin remodeling. SNIBCPS is characterized by developmental delay (DD), intellectual disability (ID), macrocephaly, and facial features including a prominent forehead and hypertelorism. Hypersociability/overfriendliness is a notable behavioral feature in patients. Here, we describe five SNIBCPS patients with CHD3 variants from four families, including a sibling pair caused by parental gonosomal mosaicism. We observed two distinct phenotypes in our patients in accordance with previous observations. Phenotype 1: macrocephaly, hypertelorism, overgrowth, DD, and ID; and Phenotype 2: microcephaly, growth retardation, DD, and ID. Phenotype 1 was consistent with the typical SNIBCPS phenotype, while Phenotype 2 was distinct. To understand further the features of the patients with SNIBCPS, we generated chd3-knockout (KO) zebrafish using CRISPR-Cas9 genome editing. No morphological changes were observed in chd3-KO zebrafish. However, behavioral tests showed that chd3-KO zebrafish had strong and sustained interest in others, and were less aggressive toward others, suggesting a recapitulation of the hypersociability/overfriendliness phenotype in patients with SNIBCPS. Metabolomic analysis using whole brains showed changes in metabolites processed by specific mitochondrial enzymes in chd3-KO zebrafish. The administration of metformin, which reportedly ameliorates mitochondrial dysfunction and behavioral abnormalities, attenuated the abnormal behavior of chd3-KO zebrafish. Our study helps delineate the phenotypes of patients with SNIBCPS, provides insights into a characteristic behavior of the disease, and suggests a potential treatment to improve the behavioral symptoms of patients.
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Affiliation(s)
- Yumi Enomoto
- Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Takashi Shiromizu
- Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Japan
- Mie University Research Center for Cilia and Diseases, Tsu, Japan
| | - Sakyo Yasojima
- Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Junko Koiwa
- Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Yukiko Kuroda
- Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Hiroaki Ito
- Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Mizuki Yuge
- Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Momoka Ohkawa
- Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Ryohei Shibata
- Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Hiroaki Murakami
- Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Takuya Naruto
- Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Shizuka Shiiya
- Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Naoko Omotani
- Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Yuhei Nishimura
- Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Japan.
- Mie University Research Center for Cilia and Diseases, Tsu, Japan.
| | - Kenji Kurosawa
- Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.
- Mie University Research Center for Cilia and Diseases, Tsu, Japan.
- Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.
- Department of Clinical Dysmorphology, Graduate School of Medicine, Mie University, Tsu, Japan.
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2
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Watzlowik MT, Silberhorn E, Das S, Singhal R, Venugopal K, Holzinger S, Stokes B, Schadt E, Sollelis L, Bonnell VA, Gow M, Klingl A, Marti M, Llinás M, Meissner M, Längst G. Plasmodium blood stage development requires the chromatin remodeller Snf2L. Nature 2025:10.1038/s41586-025-08595-x. [PMID: 39972139 DOI: 10.1038/s41586-025-08595-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 01/03/2025] [Indexed: 02/21/2025]
Abstract
The complex life cycle of the malaria parasite Plasmodium falciparum involves several major differentiation stages, each requiring strict control of gene expression. Fundamental changes in chromatin structure and epigenetic modifications during life cycle progression suggest a central role for these mechanisms in regulating the transcriptional program of malaria parasite development1-6. P. falciparum chromatin is distinct from other eukaryotes, with an extraordinarily high AT content (>80%)7 and highly divergent histones resulting in atypical DNA packaging properties8. Moreover, the chromatin remodellers that are critical for shaping chromatin structure are not conserved and are unexplored in P. falciparum. Here we identify P. falciparum Snf2L (PfSnf2L, encoded by PF3D7_1104200) as an ISWI-related ATPase that actively repositions P. falciparum nucleosomes in vitro. Our results demonstrate that PfSnf2L is essential, regulating both asexual development and sexual differentiation. PfSnf2L globally controls just-in-time transcription by spatiotemporally determining nucleosome positioning at the promoters of stage-specific genes. The unique sequence and functional properties of PfSnf2L led to the identification of an inhibitor that specifically kills P. falciparum and phenocopies the loss of correct gene expression timing. The inhibitor represents a new class of antimalarial transmission-blocking drugs, inhibiting gametocyte formation.
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Affiliation(s)
| | - Elisabeth Silberhorn
- Regensburg Center for Biochemistry (RCB), University of Regensburg, Regensburg, Germany
| | - Sujaan Das
- Experimental Parasitology, Department of Veterinary Sciences, Faculty of Veterinary Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Ritwik Singhal
- Department of Biochemistry and Molecular Biology and Huck Center for Malaria Research, Pennsylvania State University, State College, PA, USA
| | - Kannan Venugopal
- Institute of Parasitology, Vetsuisse and Medical faculty, University of Zurich, Zurich, Switzerland
- Institute of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Simon Holzinger
- Regensburg Center for Biochemistry (RCB), University of Regensburg, Regensburg, Germany
| | - Barbara Stokes
- Institute of Parasitology, Vetsuisse and Medical faculty, University of Zurich, Zurich, Switzerland
- Institute of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Ella Schadt
- Experimental Parasitology, Department of Veterinary Sciences, Faculty of Veterinary Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Lauriane Sollelis
- Institute of Parasitology, Vetsuisse and Medical faculty, University of Zurich, Zurich, Switzerland
- Institute of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Victoria A Bonnell
- Department of Biochemistry and Molecular Biology and Huck Center for Malaria Research, Pennsylvania State University, State College, PA, USA
| | - Matthew Gow
- Experimental Parasitology, Department of Veterinary Sciences, Faculty of Veterinary Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Andreas Klingl
- Plant Development, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany
| | - Matthias Marti
- Institute of Parasitology, Vetsuisse and Medical faculty, University of Zurich, Zurich, Switzerland
- Institute of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Manuel Llinás
- Department of Biochemistry and Molecular Biology and Huck Center for Malaria Research, Pennsylvania State University, State College, PA, USA
- Department of Chemistry, Pennsylvania State University, State College, PA, USA
| | - Markus Meissner
- Experimental Parasitology, Department of Veterinary Sciences, Faculty of Veterinary Medicine, Ludwig-Maximilians-University, Munich, Germany.
| | - Gernot Längst
- Regensburg Center for Biochemistry (RCB), University of Regensburg, Regensburg, Germany.
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3
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Prajapati HK, Eriksson PR, Elizalde PA, Coey CT, Xu Z, Clark DJ. The yeast genome is globally accessible in living cells. Nat Struct Mol Biol 2025; 32:247-256. [PMID: 39587299 PMCID: PMC11832417 DOI: 10.1038/s41594-024-01318-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 04/17/2024] [Indexed: 11/27/2024]
Abstract
Eukaryotic genomes are packaged into chromatin, which is composed of condensed filaments of regularly spaced nucleosomes, resembling beads on a string. The nucleosome contains ~147 bp of DNA wrapped almost twice around a central core histone octamer. The packaging of DNA into chromatin represents a challenge to transcription factors and other proteins requiring access to their binding sites. Consequently, control of DNA accessibility is thought to play a key role in gene regulation. Here we measure DNA accessibility genome wide in living budding yeast cells by inducible expression of DNA methyltransferases. We find that the genome is globally accessible in living cells, unlike in isolated nuclei, where DNA accessibility is severely restricted. Gene bodies are methylated at only slightly slower rates than promoters, indicating that yeast chromatin is highly dynamic in vivo. In contrast, silenced loci and centromeres are strongly protected. Global shifts in nucleosome positions occur in cells as they are depleted of ATP-dependent chromatin remodelers, suggesting that nucleosome dynamics result from competition among these enzymes. We conclude that chromatin is in a state of continuous flux in living cells, but static in nuclei, suggesting that DNA packaging in yeast is not generally repressive.
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Affiliation(s)
- Hemant K Prajapati
- Division of Developmental Biology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Peter R Eriksson
- Division of Developmental Biology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Paul A Elizalde
- Division of Developmental Biology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
- NIH-JHU Graduate Partnership Program, Johns Hopkins University, Baltimore, MD, USA
| | - Christopher T Coey
- Division of Developmental Biology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Zhuwei Xu
- Division of Developmental Biology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - David J Clark
- Division of Developmental Biology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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Vaswani RG, Huang DS, Anthony N, Xu L, Centore R, Schiller S, Li Z, Fan H, Setser J, Zawadzke LE, Davenport Y, Chen X, Barnash K, Adam A, Ichikawa K, Huang L, Gu CH, Voigt J, Millan D, Chan HM, Decicco C, Hentemann M, Bellon SF, Wilson KJ. Discovery of FHD-286, a First-in-Class, Orally Bioavailable, Allosteric Dual Inhibitor of the Brahma Homologue (BRM) and Brahma-Related Gene 1 (BRG1) ATPase Activity for the Treatment of SWItch/Sucrose Non-Fermentable (SWI/SNF) Dependent Cancers. J Med Chem 2025; 68:1772-1792. [PMID: 39801091 DOI: 10.1021/acs.jmedchem.4c02535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
BRM (SMARCA2) and BRG1 (SMARCA4) are mutually exclusive ATPase subunits of the mSWI/SNF (BAF) chromatin remodeling complex. BAF is an attractive therapeutic target because of its role in transcription, and mutations in the subunits of BAF are common in cancer and neurological disorders. Herein, we report the discovery of compound 1 (FHD-286) as a potent allosteric inhibitor of the dual ATPase subunits from a high-throughput screening hit with a BRM IC50 of ∼27 μM. FHD-286 is an orally bioavailable compound with antitumor activity in mouse xenograft models of uveal melanoma and acute myeloid leukemia and is being evaluated in Phase 1 clinical trials.
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Affiliation(s)
- Rishi G Vaswani
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - David S Huang
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Neville Anthony
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Lan Xu
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Richard Centore
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Shawn Schiller
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Zhifang Li
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Hong Fan
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Jeremy Setser
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Laura E Zawadzke
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Yunji Davenport
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Xueying Chen
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Kimberly Barnash
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Ammar Adam
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Kana Ichikawa
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Liyue Huang
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Chong-Hui Gu
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Johannes Voigt
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - David Millan
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Ho Man Chan
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Carl Decicco
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Martin Hentemann
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Steven F Bellon
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
| | - Kevin J Wilson
- Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States
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5
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Sultan MH, Zhan Q, Jin H, Jia X, Wang Y. Epigenetic modulation by oncolytic viruses: Implications for cancer therapeutic efficacy. Biochim Biophys Acta Rev Cancer 2025; 1880:189270. [PMID: 39855579 DOI: 10.1016/j.bbcan.2025.189270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 01/13/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025]
Abstract
Among various therapeutic agents, Oncolytic Viruses (OVs) are the most promising anticancer therapeutics because of their tumor-specific targeting and capability to mediate an antitumor immune response. In this review, we will discuss how epigenetic reprogramming of both the host and tumor can facilitate increased sensitivity of tumors to OV therapy. OVs infect tumor cells and modulate epigenetic landscapes, including DNA methylation, histone modifications, and chromatin remodeling, as well as non-coding RNA expression that consequently induces immune responses. These epigenetic changes, including hypermethylation of tumor-associated antigen genes and chromatin accessibility alterations, enhance the immunogenicity of tumors to facilitate recognition by the immune system. Here, we provide a general review addressing this question by discussing the potential benefits of combining OVs with epigenetic drugs to combat resistance and promote treatment efficacy. This information illustrates the importance of personalized OV therapy regarding epigenome in individual profiles and transitions. Still, it extends difficulty in inducing with acquisitions of viral-induced changes globally and making translatable steps by creating cancer-specific predictive treatment models.
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Affiliation(s)
- Muhammad Haris Sultan
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Qi Zhan
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Hao Jin
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Xiaoyuan Jia
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Yigang Wang
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
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6
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Kable B, Portillo-Ledesma S, Popova EY, Jentink N, Swulius M, Li Z, Schlick T, Grigoryev SA. Compromised 2-start zigzag chromatin folding in immature mouse retina cells driven by irregularly spaced nucleosomes with short DNA linkers. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.16.633430. [PMID: 39868111 PMCID: PMC11760397 DOI: 10.1101/2025.01.16.633430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
The formation of condensed heterochromatin is critical for establishing cell-specific transcriptional programs. To reveal structural transitions underlying heterochromatin formation in maturing mouse rod photoreceptors, we apply cryo-EM tomography, AI-assisted deep denoising, and molecular modeling. We find that chromatin isolated from immature retina cells contains many closely apposed nucleosomes with extremely short or absent nucleosome linkers, which are inconsistent with the typical two-start zigzag chromatin folding. In mature retina cells, the fraction of short-linker nucleosomes is much lower, supporting stronger chromatin compaction. By Cryo-EM-assisted nucleosome interaction capture we observe that chromatin in immature retina is enriched with i±1 interactions while chromatin in mature retina contains predominantly i±2 interactions typical of the two-start zigzag. By mesoscale modeling and computational simulation, we clarify that the unusually short linkers typical of immature retina are sufficient to inhibit the two-start zigzag and chromatin compaction by the interference of very short linkers with linker DNA stems. We propose that this short linker composition renders nucleosome arrays more open in immature retina and that, as the linker DNA length increases in mature retina, chromatin fibers become globally condensed via tight zigzag folding. This mechanism may be broadly utilized to introduce higher chromatin folding entropy for epigenomic plasticity.
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7
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Malik D, Deshmukh A, Bilokapic S, Halic M. Mechanisms of chromatin remodeling by an Snf2-type ATPase. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.12.31.630910. [PMID: 39803580 PMCID: PMC11722347 DOI: 10.1101/2024.12.31.630910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
Chromatin remodeling enzymes play a crucial role in the organization of chromatin, enabling both stability and plasticity of genome regulation. These enzymes use a Snf2-type ATPase motor to move nucleosomes, but how they translocate DNA around the histone octamer is unclear. Here we use cryo-EM to visualize the continuous motion of nucleosomal DNA induced by human chromatin remodeler SNF2H, an ISWI family member. Our work reveals conformational changes in SNF2H, DNA and histones during nucleosome sliding and provides the structural basis for DNA translocation. ATP hydrolysis induces conformational changes in SNF2H that pull the DNA tracking strand, distorting DNA and histones at SHL2. This is followed by SNF2H rotation on the nucleosome, which first pulls the DNA guide strand and creates one-base pair bulge at SHL2, and then releases the pulled DNA. Given the high conservation of the catalytic motors among ATP-dependent chromatin remodelers, the mechanisms we describe likely apply to other families.
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Affiliation(s)
- Deepshikha Malik
- Department of Structural Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Ashish Deshmukh
- Department of Structural Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Silvija Bilokapic
- Department of Structural Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Mario Halic
- Department of Structural Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
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8
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Fendler NL, Ly J, Welp L, Lu D, Schulte F, Urlaub H, Vos SM. Identification and characterization of a human MORC2 DNA binding region that is required for gene silencing. Nucleic Acids Res 2024:gkae1273. [PMID: 39739841 DOI: 10.1093/nar/gkae1273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 11/06/2024] [Accepted: 12/12/2024] [Indexed: 01/02/2025] Open
Abstract
The eukaryotic microrchidia (MORC) protein family are DNA gyrase, Hsp90, histidine kinase, MutL (GHKL)-type ATPases involved in gene expression regulation and chromatin compaction. The molecular mechanisms underlying these activities are incompletely understood. Here, we studied the full-length human MORC2 protein biochemically. We identified a DNA binding site in the C-terminus of the protein, and we observe that this region can be phosphorylated in cells. DNA binding by MORC2 reduces its ATPase activity and MORC2 can entrap multiple DNA substrates between its N-terminal GHKL and C-terminal coiled coil 3 dimerization domains. Finally, we observe that the MORC2 C-terminal DNA binding region is required for gene silencing in cells. Together, our data provide a model to understand how MORC2 engages with DNA substrates to mediate gene silencing.
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Affiliation(s)
- Nikole L Fendler
- Department of Biology, Massachusetts Institute of Technology, Building 68, 31 Ames St., Cambridge, MA 02139, USA
| | - Jimmy Ly
- Department of Biology, Massachusetts Institute of Technology, Building 68, 31 Ames St., Cambridge, MA 02139, USA
- Whitehead Institute for Biomedical Research, 455 Main St, Cambridge, MA 02139, USA
| | - Luisa Welp
- Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, 37077 Göttingen, Germany
- Department of Clinical Chemistry, Bioanalytics Group, University Medical Center Göttingen, Robert-Koch-Straße 40 37075 Göttingen, Germany
| | - Dan Lu
- Department of Systems Biology, Harvard Medical School, 210 Longwood Avenue, Boston, MA 02115, USA
| | - Fabian Schulte
- Whitehead Institute for Biomedical Research, Quantitative Proteomics Core, 455 Main St, Cambridge, MA 02139, USA
| | - Henning Urlaub
- Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, 37077 Göttingen, Germany
- Department of Clinical Chemistry, Bioanalytics Group, University Medical Center Göttingen, Robert-Koch-Straße 40 37075 Göttingen, Germany
| | - Seychelle M Vos
- Department of Biology, Massachusetts Institute of Technology, Building 68, 31 Ames St., Cambridge, MA 02139, USA
- Howard Hughes Medical Institute, 4000 Jones Bridge Rd, Chevy Chase, MD 20815, USA
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9
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Burdusel D, Doeppner TR, Surugiu R, Hermann DM, Olaru DG, Popa-Wagner A. The Intersection of Epigenetics and Senolytics in Mechanisms of Aging and Therapeutic Approaches. Biomolecules 2024; 15:18. [PMID: 39858413 PMCID: PMC11762397 DOI: 10.3390/biom15010018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/11/2024] [Accepted: 12/23/2024] [Indexed: 01/27/2025] Open
Abstract
The biological process of aging is influenced by a complex interplay of genetic, environmental, and epigenetic factors. Recent advancements in the fields of epigenetics and senolytics offer promising avenues for understanding and addressing age-related diseases. Epigenetics refers to heritable changes in gene expression without altering the DNA sequence, with mechanisms like DNA methylation, histone modification, and non-coding RNA regulation playing critical roles in aging. Senolytics, a class of drugs targeting and eliminating senescent cells, address the accumulation of dysfunctional cells that contribute to tissue degradation and chronic inflammation through the senescence-associated secretory phenotype. This scoping review examines the intersection of epigenetic mechanisms and senolytic therapies in aging, focusing on their combined potential for therapeutic interventions. Senescent cells display distinct epigenetic signatures, such as DNA hypermethylation and histone modifications, which can be targeted to enhance senolytic efficacy. Epigenetic reprogramming strategies, such as induced pluripotent stem cells, may further complement senolytics by rejuvenating aged cells. Integrating epigenetic modulation with senolytic therapy offers a dual approach to improving healthspan and mitigating age-related pathologies. This narrative review underscores the need for continued research into the molecular mechanisms underlying these interactions and suggests future directions for therapeutic development, including clinical trials, biomarker discovery, and combination therapies that synergistically target aging processes.
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Affiliation(s)
- Daiana Burdusel
- Experimental Research Center for Normal and Pathological Aging, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania; (D.B.); (R.S.); (D.M.H.)
| | - Thorsten R. Doeppner
- Department of Neurology, University of Giessen Medical School, 35392 Giessen, Germany;
- Department of Neurology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Roxana Surugiu
- Experimental Research Center for Normal and Pathological Aging, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania; (D.B.); (R.S.); (D.M.H.)
| | - Dirk M. Hermann
- Experimental Research Center for Normal and Pathological Aging, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania; (D.B.); (R.S.); (D.M.H.)
- Chair of Vascular Neurology and Dementia, Department of Neurology, University Hospital Essen, 45147 Essen, Germany
| | - Denissa Greta Olaru
- Experimental Research Center for Normal and Pathological Aging, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania; (D.B.); (R.S.); (D.M.H.)
| | - Aurel Popa-Wagner
- Experimental Research Center for Normal and Pathological Aging, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania; (D.B.); (R.S.); (D.M.H.)
- Chair of Vascular Neurology and Dementia, Department of Neurology, University Hospital Essen, 45147 Essen, Germany
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10
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Cao Z, Wolynes PG. Chromatin folding through nonuniform motorization by responsive motor proteins. J Chem Phys 2024; 161:224903. [PMID: 39651819 DOI: 10.1063/5.0238294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 11/26/2024] [Indexed: 12/11/2024] Open
Abstract
Chromatin is partially structured through the effects of biological motors. "Swimming motors" such as RNA polymerases and chromatin remodelers are thought to act differentially on the active parts of the genome and the stored inactive part. By systematically expanding the many-body master equation for chromosomes driven by swimming motors, we show that this nonuniform aspect of motorization leads to heterogeneously folded conformations, thereby contributing to chromosome compartmentalization.
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Affiliation(s)
- Zhiyu Cao
- Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005, USA
| | - Peter G Wolynes
- Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005, USA
- Department of Chemistry, Rice University, Houston, Texas 77005, USA
- Department of Physics, Rice University, Houston, Texas 77005, USA
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11
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Feng S, Liu K, Shang J, Hoeg L, Pastore G, Yang W, Roy S, Sastre-Moreno G, Young JTF, Wu W, Xu D, Durocher D. Profound synthetic lethality between SMARCAL1 and FANCM. Mol Cell 2024; 84:4522-4537.e7. [PMID: 39510066 DOI: 10.1016/j.molcel.2024.10.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 09/06/2024] [Accepted: 10/11/2024] [Indexed: 11/15/2024]
Abstract
DNA replication stress is a threat to genome integrity. The large SNF2-family of ATPases participates in preventing and mitigating DNA replication stress by employing their ATP-driven motor to remodel DNA or DNA-bound proteins. To understand the contribution of these ATPases in genome maintenance, we undertook CRISPR-based synthetic lethality screens in human cells with three SNF2-type ATPases: SMARCAL1, ZRANB3, and HLTF. Here, we show that SMARCAL1 displays a profound synthetic-lethal interaction with FANCM, another ATP-dependent translocase involved in DNA replication and genome stability. Their combined loss causes severe genome instability that we link to chromosome breakage at loci enriched in simple repeats, which are known to challenge replication fork progression. Our findings illuminate a critical genetic buffering mechanism that provides an essential function for maintaining genome integrity.
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Affiliation(s)
- Sumin Feng
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada
| | - Kaiwen Liu
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
| | - Jinfeng Shang
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
| | - Lisa Hoeg
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada
| | - Graziana Pastore
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada
| | - William Yang
- Repare Therapeutics, 7171 rue Frederick Banting, Saint-Laurent, QC H4S 1Z9, Canada
| | - Sabrina Roy
- Repare Therapeutics, 7171 rue Frederick Banting, Saint-Laurent, QC H4S 1Z9, Canada
| | - Guillermo Sastre-Moreno
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada
| | - Jordan T F Young
- Repare Therapeutics, 7171 rue Frederick Banting, Saint-Laurent, QC H4S 1Z9, Canada
| | - Wei Wu
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Dongyi Xu
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
| | - Daniel Durocher
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
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12
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Huang Y, Yang X, Wang Y, Nai Y, Ji L, Zhu H, Lai R, Wang QT, Hu H, Wang L. ARID1A recruits GATA2 to regulate the senescence of trophoblast cells under high-glucose condition. Placenta 2024; 158:156-164. [PMID: 39490111 DOI: 10.1016/j.placenta.2024.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 10/02/2024] [Accepted: 10/20/2024] [Indexed: 11/05/2024]
Abstract
INTRODUCTION Gestational diabetes mellitus (GDM) is a common complication during pregnancy. The hyperglycemic stimulation of gestational diabetes inhibits the invasion of the placental trophoblast cells. Some studies have indicated that the senescence of trophoblast cells weakens their invasive capacity, while the mechanism of trophoblast cells senescence in GDM remain elusive. METHODS We performed western blotting and Immunohistochemical staining to investigate AT-Rich Interaction Domain 1A (ARID1A) expression in GDM placental tissues. 5 mM and 30 mM glucose treated HTR-8/SVneo cells to simulate normal glucose (NG) stress and high glucose (HG) stress. Cell proliferation capacity was investigated by CCK8 assay and cell cycle assay. SA-β-gal was used to detect cellular senescence. Chip-seq characterized the binding site of ARID1A to CDKN1A. In conjunction with bioinformatics analysis, co-immunoprecipitation assays, Chip-qPCR and luciferase reporter assays were performed to prove ARID1A recruits GATA2 to CDKN1A. RESULTS We found that ARID1A has a higher expression levels in GDM placental tissues compared to the control. ARID1A overexpression suppressed cell proliferation, induced cell cycle arrest and promoted cell senescence. Conversely the inhibition of ARID1A significantly rescues HG induced senescence of trophoblast cells. To further characterize the mechanism by which ARID1A regulate the transcription of CDKN1A, co-immunoprecipitation assays, Chip-qPCR and luciferase reporter assay indicate that ARID1A recruits GATA2 to regulate the transcriptional activity of CDKN1A. DISCUSSION Our study uncovers a ARID1A mediated regulatory mechanism in GDM trophoblast cell senescence and suggests that targeting the placental ARID1A might provide new diagnostic and therapeutic strategies for GDM.
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Affiliation(s)
- Yanyi Huang
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Xiting Yang
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yuexiao Wang
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yaru Nai
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Lulu Ji
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Hengxuan Zhu
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Rujie Lai
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Qiong Tao Wang
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Hanyang Hu
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
| | - Lin Wang
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
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13
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Chakraborty P, Mukherjee C. The interplay of metabolic and epigenetic players in disease development. Biochem Biophys Res Commun 2024; 734:150621. [PMID: 39217811 DOI: 10.1016/j.bbrc.2024.150621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 08/14/2024] [Accepted: 08/28/2024] [Indexed: 09/04/2024]
Abstract
Epigenetic modifications and their alterations can cause variation in gene expression patterns which can ultimately affect a healthy individual. Until a few years ago, it was thought that the epigenome affects the transcriptome which can regulate the proteome and the metabolome. Recent studies have shown that the metabolome independently also plays a major role in regulating the epigenome bypassing the need for transcriptomic control. Alternatively, an imbalanced metabolome, stemming from transcriptome abnormalities, can further impact the transcriptome, creating a self-perpetuating cycle of interconnected occurrences. As a result, external factors such as nutrient intake and diet can have a direct impact on the metabolic pools and its reprogramming can change the levels and activity of epigenetic modifiers. Thus, the epigenetic landscape steers toward a diseased condition. In this review, we have discussed how different metabolites and dietary patterns can bring about changes in different arms of the epigenetic machinery such as methylation, acetylation as well as RNA mediated epigenetic mechanisms. We checked for limiting metabolites such as αKG, acetyl-CoA, ATP, NAD+, and FAD, whose abundance levels can lead to common diseases such as cancer, neurodegeneration etc. This gives a clearer picture of how an integrated approach including both epigenetics and metabolomics can be used for therapeutic purposes.
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Affiliation(s)
- Pallavi Chakraborty
- RNABio Lab, Institute of Health Sciences, Presidency University, Kolkata, West Bengal, India; Shiv Nadar Institute of Eminence, Greater Noida, Uttar Pradesh, India
| | - Chandrama Mukherjee
- RNABio Lab, Institute of Health Sciences, Presidency University, Kolkata, West Bengal, India.
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14
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Dutta S, Sengupta P, Mottola F, Das S, Hussain A, Ashour A, Rocco L, Govindasamy K, Rosas IM, Roychoudhury S. Crosstalk Between Oxidative Stress and Epigenetics: Unveiling New Biomarkers in Human Infertility. Cells 2024; 13:1846. [PMID: 39594595 PMCID: PMC11593296 DOI: 10.3390/cells13221846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/28/2024] [Accepted: 11/03/2024] [Indexed: 11/28/2024] Open
Abstract
The correlation between epigenetic alterations and the pathophysiology of human infertility is progressively being elucidated with the discovery of an increasing number of target genes that exhibit altered expression patterns linked to reproductive abnormalities. Several genes and molecules are emerging as important for the future management of human infertility. In men, microRNAs (miRNAs) like miR-34c, miR-34b, and miR-122 regulate apoptosis, sperm production, and germ cell survival, while other factors, such as miR-449 and sirtuin 1 (SIRT1), influence testicular health, oxidative stress, and mitochondrial function. In women, miR-100-5p, miR-483-5p, and miR-486-5p are linked to ovarian reserve, PCOS, and conditions like endometriosis. Mechanisms such as DNA methylation, histone modification, chromatin restructuring, and the influence of these non-coding RNA (ncRNA) molecules have been identified as potential perturbators of normal spermatogenesis and oogenesis processes. In fact, alteration of these key regulators of epigenetic processes can lead to reproductive disorders such as defective spermatogenesis, failure of oocyte maturation and embryonic development alteration. One of the primary factors contributing to changes in the key epigenetic regulators appear to be oxidative stress, which arises from environmental exposure to toxic substances or unhealthy lifestyle choices. This evidence-based study, retracing the major epigenetic processes, aims to identify and discuss the main epigenetic biomarkers of male and female fertility associated with an oxidative imbalance, providing future perspectives in the diagnosis and management of infertile couples.
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Affiliation(s)
- Sulagna Dutta
- Basic Medical Sciences Department, College of Medicine, Ajman University, Ajman 346, United Arab Emirates
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman 346, United Arab Emirates
| | - Pallav Sengupta
- Department of Biomedical Sciences, College of Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates
| | - Filomena Mottola
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, 81100 Caserta, Italy
| | - Sandipan Das
- Department of Life Science and Bioinformatics, Assam University, Silchar 788011, India
| | - Arif Hussain
- School of Life Sciences, Manipal Academy of Higher Education (MAHE), Dubai 345050, United Arab Emirates
| | - Ahmed Ashour
- Department of Biomedical Sciences, College of Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates
| | - Lucia Rocco
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, 81100 Caserta, Italy
| | - Kadirvel Govindasamy
- ICAR-Agricultural Technology Application Research Institute, Guwahati 781017, India
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15
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Stoler-Barak L, Schmiedel D, Sarusi-Portuguez A, Rogel A, Blecher-Gonen R, Haimon Z, Stopka T, Shulman Z. SMARCA5-mediated chromatin remodeling is required for germinal center formation. J Exp Med 2024; 221:e20240433. [PMID: 39297882 PMCID: PMC11413417 DOI: 10.1084/jem.20240433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 06/19/2024] [Accepted: 08/15/2024] [Indexed: 09/26/2024] Open
Abstract
The establishment of long-lasting immunity against pathogens is facilitated by the germinal center (GC) reaction, during which B cells increase their antibody affinity and differentiate into antibody-secreting cells (ASC) and memory cells. These events involve modifications in chromatin packaging that orchestrate the profound restructuring of gene expression networks that determine cell fate. While several chromatin remodelers were implicated in lymphocyte functions, less is known about SMARCA5. Here, using ribosomal pull-down for analyzing translated genes in GC B cells, coupled with functional experiments in mice, we identified SMARCA5 as a key chromatin remodeler in B cells. While the naive B cell compartment remained unaffected following conditional depletion of Smarca5, effective proliferation during B cell activation, immunoglobulin class switching, and as a result GC formation and ASC differentiation were impaired. Single-cell multiomic sequencing analyses revealed that SMARCA5 is crucial for facilitating the transcriptional modifications and genomic accessibility of genes that support B cell activation and differentiation. These findings offer novel insights into the functions of SMARCA5, which can be targeted in various human pathologies.
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Affiliation(s)
- Liat Stoler-Barak
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Dominik Schmiedel
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Avital Sarusi-Portuguez
- Mantoux Bioinformatics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Adi Rogel
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Ronnie Blecher-Gonen
- The Crown Genomics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Zhana Haimon
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Tomas Stopka
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Ziv Shulman
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel
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16
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Nocente MC, Mesihovic Karamitsos A, Drouineau E, Soleil M, Albawardi W, Dulary C, Ribierre F, Picaud H, Alibert O, Acker J, Kervella M, Aude JC, Gilbert N, Ochsenbein F, Chantalat S, Gérard M. cBAF generates subnucleosomes that expand OCT4 binding and function beyond DNA motifs at enhancers. Nat Struct Mol Biol 2024; 31:1756-1768. [PMID: 38956169 DOI: 10.1038/s41594-024-01344-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/03/2024] [Indexed: 07/04/2024]
Abstract
The canonical BRG/BRM-associated factor (cBAF) complex is essential for chromatin opening at enhancers in mammalian cells. However, the nature of the open chromatin remains unclear. Here, we show that, in addition to producing histone-free DNA, cBAF generates stable hemisome-like subnucleosomal particles containing the four core histones associated with 50-80 bp of DNA. Our genome-wide analysis indicates that cBAF makes these particles by targeting and splitting fragile nucleosomes. In mouse embryonic stem cells, these subnucleosomes become an in vivo binding substrate for the master transcription factor OCT4 independently of the presence of OCT4 DNA motifs. At enhancers, the OCT4-subnucleosome interaction increases OCT4 occupancy and amplifies the genomic interval bound by OCT4 by up to one order of magnitude compared to the region occupied on histone-free DNA. We propose that cBAF-dependent subnucleosomes orchestrate a molecular mechanism that projects OCT4 function in chromatin opening beyond its DNA motifs.
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Affiliation(s)
- Marina C Nocente
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France
| | - Anida Mesihovic Karamitsos
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France
| | - Emilie Drouineau
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France
| | - Manon Soleil
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France
| | - Waad Albawardi
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Cécile Dulary
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Evry, France
| | - Florence Ribierre
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Evry, France
| | - Hélène Picaud
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France
| | - Olivier Alibert
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Evry, France
| | - Joël Acker
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France
| | - Marie Kervella
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France
| | - Jean-Christophe Aude
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France
| | - Nick Gilbert
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Françoise Ochsenbein
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France
| | - Sophie Chantalat
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Evry, France
| | - Matthieu Gérard
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France.
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17
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Chen LL. Linking a Neurodevelopmental Disorder with a lncRNA Deletion. N Engl J Med 2024; 391:1542-1545. [PMID: 39442046 DOI: 10.1056/nejme2411291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Affiliation(s)
- Ling-Ling Chen
- From the Laboratory of RNA Innovation, Science, and Engineering, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, and the Cornerstone Science Laboratory, Shenzhen - both in China
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18
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Shin Y. Histone Tail Cleavage as a Mechanism for Epigenetic Regulation. Int J Mol Sci 2024; 25:10789. [PMID: 39409117 PMCID: PMC11477362 DOI: 10.3390/ijms251910789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 09/30/2024] [Indexed: 10/20/2024] Open
Abstract
Histones are essential for DNA packaging and undergo post-translational modifications that significantly influence gene regulation. Among these modifications, histone tail cleavage has recently garnered attention despite being less explored. Cleavage by various proteases impacts processes such as stem cell differentiation, aging, infection, and inflammation, though the mechanisms remain unclear. This review delves into recent insights on histone proteolytic cleavage and its epigenetic significance, highlighting how chromatin, which serves as a dynamic scaffold, responds to signals through histone modification, replacement, and ATP-dependent remodeling. Specifically, histone tail cleavage is linked to critical cellular processes such as granulocyte differentiation, viral infection, aging, yeast sporulation, and cancer development. Although the exact mechanisms connecting histone cleavage to gene expression are still emerging, it is clear that this process represents a novel epigenetic transcriptional mechanism intertwined with chromatin dynamics. This review explores known histone tail cleavage events, the proteolytic enzymes involved, their impact on gene expression, and future research directions in this evolving field.
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Affiliation(s)
- Yonghwan Shin
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA
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19
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Andrikopoulos PC, Čabart P. The chromatin remodeler SMARCA5 binds to d-block metal supports: Characterization of affinities by IMAC chromatography and QM analysis. PLoS One 2024; 19:e0309134. [PMID: 39374200 PMCID: PMC11458017 DOI: 10.1371/journal.pone.0309134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/05/2024] [Indexed: 10/09/2024] Open
Abstract
The ISWI family protein SMARCA5 contains the ATP-binding pocket that coordinates the catalytic Mg2+ ion and water molecules for ATP hydrolysis. In this study, we demonstrate that SMARCA5 can also possess an alternative metal-binding ability. First, we isolated SMARCA5 on the cobalt column (IMAC) to near homogeneity. Examination of the interactions of SMARCA5 with metal-chelating supports showed that, apart from Co2+, it binds to Cu2+, Zn2+ and Ni2+. The efficiency of the binding to the last-listed metal was influenced by the chelating ligand, resulting in a strong preference for Ni-NTA over the Ni-CM-Asp equivalent. To gain insight in the preferential affinity for the Ni-NTA ligand, QM calculations were performed on model systems and metal-ligand complexes with a limited protein fragment of SMARCA5 containing the double-histidine (dHis) motif. The calculations correlated the observed affinity with the relative stability of the d-block metals to tetradentate ligand coordination over tridentate, as well as their overall octahedral coordination capacity. Likewise, binding free energies derived from model imidazole complexes mirrored the observed Ni-NTA/Ni-CM-Asp preferential affinity. Finally, similar calculations on complexes with a SMARCA5 peptide fragment derived from the AlphaFold structural prediction, captured almost accurately the expected relative stability of the TM complexes, and produced a large energetic separation (~10 kcal∙mol-1) between Ni-NTA and Ni-CM-Asp in favour of the former.
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Affiliation(s)
- Prokopis C. Andrikopoulos
- BIOCEV, Institute of Biotechnology of the Czech Academy of Sciences, Vestec, Czechia
- BIOCEV, 1 Faculty of Medicine, Charles University, Vestec, Czechia
| | - Pavel Čabart
- Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
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20
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Abu Sailik F, Emerald BS, Ansari SA. Opening and changing: mammalian SWI/SNF complexes in organ development and carcinogenesis. Open Biol 2024; 14:240039. [PMID: 39471843 PMCID: PMC11521604 DOI: 10.1098/rsob.240039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 07/04/2024] [Accepted: 09/18/2024] [Indexed: 11/01/2024] Open
Abstract
The switch/sucrose non-fermentable (SWI/SNF) subfamily are evolutionarily conserved, ATP-dependent chromatin-remodelling complexes that alter nucleosome position and regulate a spectrum of nuclear processes, including gene expression, DNA replication, DNA damage repair, genome stability and tumour suppression. These complexes, through their ATP-dependent chromatin remodelling, contribute to the dynamic regulation of genetic information and the maintenance of cellular processes essential for normal cellular function and overall genomic integrity. Mutations in SWI/SNF subunits are detected in 25% of human malignancies, indicating that efficient functioning of this complex is required to prevent tumourigenesis in diverse tissues. During development, SWI/SNF subunits help establish and maintain gene expression patterns essential for proper cellular identity and function, including maintenance of lineage-specific enhancers. Moreover, specific molecular signatures associated with SWI/SNF mutations, including disruption of SWI/SNF activity at enhancers, evasion of G0 cell cycle arrest, induction of cellular plasticity through pro-oncogene activation and Polycomb group (PcG) complex antagonism, are linked to the initiation and progression of carcinogenesis. Here, we review the molecular insights into the aetiology of human malignancies driven by disruption of the SWI/SNF complex and correlate these mechanisms to their developmental functions. Finally, we discuss the therapeutic potential of targeting SWI/SNF subunits in cancer.
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Affiliation(s)
- Fadia Abu Sailik
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE
| | - Bright Starling Emerald
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE
- ASPIRE Precision Medicine Research Institute Abu Dhabi (PMRI-AD), United Arab Emirates University, Al Ain, Abu Dhabi, UAE
| | - Suraiya Anjum Ansari
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE
- ASPIRE Precision Medicine Research Institute Abu Dhabi (PMRI-AD), United Arab Emirates University, Al Ain, Abu Dhabi, UAE
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21
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Zanetti ME, Blanco F, Ferrari M, Ariel F, Benoit M, Niebel A, Crespi M. Epigenetic control during root development and symbiosis. PLANT PHYSIOLOGY 2024; 196:697-710. [PMID: 38865442 DOI: 10.1093/plphys/kiae333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 05/02/2024] [Accepted: 05/24/2024] [Indexed: 06/14/2024]
Abstract
The roots of plants play multiple functions that are essential for growth and development, including anchoring to the soil as well as water and nutrient acquisition. These underground organs exhibit the plasticity to modify their root system architecture in response to environmental cues, allowing adaptation to change in water and nutrient availability. In addition, roots enter in mutualistic interactions with soil microorganisms, for example, the root nodule symbiosis (RNS) established between a limited group of plants and nitrogen-fixing soil bacteria and the arbuscular mycorrhiza symbiosis involving most land plants and fungi of the Glomeromycetes phylum. In the past 20 years, genetic approaches allowed the identification and functional characterization of genes required for the specific programs of root development, root nodule, and arbuscular mycorrhiza symbioses. These genetic studies provided evidence that the program of the RNS recruited components of the arbuscular mycorrhiza symbiosis and the root developmental programs. The execution of these programs is strongly influenced by epigenetic changes-DNA methylation and histone post-translational modifications-that alter chromatin conformation modifying the expression of key genes. In this review, we summarize recent advances that highlight how DNA methylation and histone post-translational modifications, as well as chromatin remodeling factors and long noncoding RNAs, shape the root system architecture and allow the successful establishment of both root nodule and arbuscular mycorrhiza symbioses. We anticipate that the analysis of dynamic epigenetic changes and chromatin 3D structure in specific single cells or tissue types of root organs will illuminate our understanding of how root developmental and symbiotic programs are orchestrated, opening exciting questions and new perspectives to modulate agronomical and ecological traits linked to nutrient acquisition.
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Affiliation(s)
- María Eugenia Zanetti
- Instituto de Biotecnología y Biología Molecular, Facultad de Ciencias Exactas, Universidad Nacional de La Plata and Centro Científico y Tecnológico-La Plata, Consejo Nacional de Investigaciones Científicas y Técnicas, La Plata 1900, Argentina
| | - Flavio Blanco
- Instituto de Biotecnología y Biología Molecular, Facultad de Ciencias Exactas, Universidad Nacional de La Plata and Centro Científico y Tecnológico-La Plata, Consejo Nacional de Investigaciones Científicas y Técnicas, La Plata 1900, Argentina
| | - Milagros Ferrari
- Instituto de Biotecnología y Biología Molecular, Facultad de Ciencias Exactas, Universidad Nacional de La Plata and Centro Científico y Tecnológico-La Plata, Consejo Nacional de Investigaciones Científicas y Técnicas, La Plata 1900, Argentina
| | - Federico Ariel
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Universidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, and Consejo Nacional de Investigaciones Científicas y Técnicas CONICET, Buenos Aires C1428EGA, Argentina
| | - Matthias Benoit
- Laboratoire des Interactions Plantes-Microorganismes (LIPME), INRAE, CNRS, Université de Toulouse, INRAE, CNRS, Castanet-Tolosan 31326, France
| | - Andreas Niebel
- Laboratoire des Interactions Plantes-Microorganismes (LIPME), INRAE, CNRS, Université de Toulouse, INRAE, CNRS, Castanet-Tolosan 31326, France
| | - Martin Crespi
- Université Paris-Saclay, CNRS, INRAE, Université Evry, Institute of Plant Sciences Paris-Saclay (IPS2), Gif sur Yvette 91190, France
- Université Paris Cité, Institute of Plant Sciences Paris-Saclay (IPS2), Gif sur Yvette 91190, France
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22
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Engl W, Kunstar-Thomas A, Chen S, Ng WS, Sielaff H, Zhao ZW. Single-molecule imaging of SWI/SNF chromatin remodelers reveals bromodomain-mediated and cancer-mutants-specific landscape of multi-modal DNA-binding dynamics. Nat Commun 2024; 15:7646. [PMID: 39223123 PMCID: PMC11369179 DOI: 10.1038/s41467-024-52040-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 08/22/2024] [Indexed: 09/04/2024] Open
Abstract
Despite their prevalent cancer implications, the in vivo dynamics of SWI/SNF chromatin remodelers and how misregulation of such dynamics underpins cancer remain poorly understood. Using live-cell single-molecule tracking, we quantify the intranuclear diffusion and chromatin-binding of three key subunits common to all major human SWI/SNF remodeler complexes (BAF57, BAF155 and BRG1), and resolve two temporally distinct stable binding modes for the fully assembled complex. Super-resolved density mapping reveals heterogeneous, nanoscale remodeler binding "hotspots" across the nucleoplasm where multiple binding events (especially longer-lived ones) preferentially cluster. Importantly, we uncover distinct roles of the bromodomain in modulating chromatin binding/targeting in a DNA-accessibility-dependent manner, pointing to a model where successive longer-lived binding within "hotspots" leads to sustained productive remodeling. Finally, systematic comparison of six common BRG1 mutants implicated in various cancers unveils alterations in chromatin-binding dynamics unique to each mutant, shedding insight into a multi-modal landscape regulating the spatio-temporal organizational dynamics of SWI/SNF remodelers.
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Affiliation(s)
- Wilfried Engl
- Department of Chemistry, Faculty of Science, National University of Singapore, Singapore, 119543, Singapore
- Centre for BioImaging Sciences, Faculty of Science, National University of Singapore, Singapore, 117557, Singapore
| | - Aliz Kunstar-Thomas
- Department of Chemistry, Faculty of Science, National University of Singapore, Singapore, 119543, Singapore
- Centre for BioImaging Sciences, Faculty of Science, National University of Singapore, Singapore, 117557, Singapore
| | - Siyi Chen
- Department of Chemistry, Faculty of Science, National University of Singapore, Singapore, 119543, Singapore
- Centre for BioImaging Sciences, Faculty of Science, National University of Singapore, Singapore, 117557, Singapore
| | - Woei Shyuan Ng
- Department of Chemistry, Faculty of Science, National University of Singapore, Singapore, 119543, Singapore
- Centre for BioImaging Sciences, Faculty of Science, National University of Singapore, Singapore, 117557, Singapore
| | - Hendrik Sielaff
- Department of Chemistry, Faculty of Science, National University of Singapore, Singapore, 119543, Singapore
- Centre for BioImaging Sciences, Faculty of Science, National University of Singapore, Singapore, 117557, Singapore
| | - Ziqing Winston Zhao
- Department of Chemistry, Faculty of Science, National University of Singapore, Singapore, 119543, Singapore.
- Centre for BioImaging Sciences, Faculty of Science, National University of Singapore, Singapore, 117557, Singapore.
- Mechanobiology Institute, National University of Singapore, Singapore, 117411, Singapore.
- Integrative Sciences and Engineering Programme, National University of Singapore, Singapore, 119077, Singapore.
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23
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Malone HA, Roberts CWM. Chromatin remodellers as therapeutic targets. Nat Rev Drug Discov 2024; 23:661-681. [PMID: 39014081 PMCID: PMC11534152 DOI: 10.1038/s41573-024-00978-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/28/2024] [Indexed: 07/18/2024]
Abstract
Large-scale cancer genome sequencing studies have revealed that chromatin regulators are frequently mutated in cancer. In particular, more than 20% of cancers harbour mutations in genes that encode subunits of SWI/SNF (BAF) chromatin remodelling complexes. Additional links of SWI/SNF complexes to disease have emerged with the findings that some oncogenes drive transformation by co-opting SWI/SNF function and that germline mutations in select SWI/SNF subunits are the basis of several neurodevelopmental disorders. Other chromatin remodellers, including members of the ISWI, CHD and INO80/SWR complexes, have also been linked to cancer and developmental disorders. Consequently, therapeutic manipulation of SWI/SNF and other remodelling complexes has become of great interest, and drugs that target SWI/SNF subunits have entered clinical trials. Genome-wide perturbation screens in cancer cell lines with SWI/SNF mutations have identified additional synthetic lethal targets and led to further compounds in clinical trials, including one that has progressed to FDA approval. Here, we review the progress in understanding the structure and function of SWI/SNF and other chromatin remodelling complexes, mechanisms by which SWI/SNF mutations cause cancer and neurological diseases, vulnerabilities that arise because of these mutations and efforts to target SWI/SNF complexes and synthetic lethal targets for therapeutic benefit.
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Affiliation(s)
- Hayden A Malone
- Division of Molecular Oncology, Department of Oncology, and Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, TN, USA
- St. Jude Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Charles W M Roberts
- Division of Molecular Oncology, Department of Oncology, and Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, TN, USA.
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24
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Goychuk A, Kannan D, Kardar M. Delayed Excitations Induce Polymer Looping and Coherent Motion. PHYSICAL REVIEW LETTERS 2024; 133:078101. [PMID: 39213554 DOI: 10.1103/physrevlett.133.078101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 06/25/2024] [Accepted: 07/12/2024] [Indexed: 09/04/2024]
Abstract
We consider inhomogeneous polymers driven by energy-consuming active processes which encode temporal patterns of athermal kicks. We find that such temporal excitation programs, propagated by tension along the polymer, can effectively couple distinct polymer loci. Consequently, distant loci exhibit correlated motions that fold the polymer into specific conformations, as set by the local actions of the active processes and their distribution along the polymer. Interestingly, active kicks that are canceled out by a time-delayed echo can induce strong compaction of the active polymer.
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25
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Liang J, Xiao K, Wang X, Hou T, Zeng C, Gao X, Wang B, Zhong C. Revisiting Solar Energy Flow in Nanomaterial-Microorganism Hybrid Systems. Chem Rev 2024; 124:9081-9112. [PMID: 38900019 DOI: 10.1021/acs.chemrev.3c00831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Nanomaterial-microorganism hybrid systems (NMHSs), integrating semiconductor nanomaterials with microorganisms, present a promising platform for broadband solar energy harvesting, high-efficiency carbon reduction, and sustainable chemical production. While studies underscore its potential in diverse solar-to-chemical energy conversions, prevailing NMHSs grapple with suboptimal energy conversion efficiency. Such limitations stem predominantly from an insufficient systematic exploration of the mechanisms dictating solar energy flow. This review provides a systematic overview of the notable advancements in this nascent field, with a particular focus on the discussion of three pivotal steps of energy flow: solar energy capture, cross-membrane energy transport, and energy conversion into chemicals. While key challenges faced in each stage are independently identified and discussed, viable solutions are correspondingly postulated. In view of the interplay of the three steps in affecting the overall efficiency of solar-to-chemical energy conversion, subsequent discussions thus take an integrative and systematic viewpoint to comprehend, analyze and improve the solar energy flow in the current NMHSs of different configurations, and highlighting the contemporary techniques that can be employed to investigate various aspects of energy flow within NMHSs. Finally, a concluding section summarizes opportunities for future research, providing a roadmap for the continued development and optimization of NMHSs.
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Affiliation(s)
- Jun Liang
- Key Laboratory of Quantitative Synthetic Biology, Center for Materials Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Kemeng Xiao
- Key Laboratory of Quantitative Synthetic Biology, Center for Materials Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Xinyu Wang
- Key Laboratory of Quantitative Synthetic Biology, Center for Materials Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Tianfeng Hou
- Key Laboratory of Quantitative Synthetic Biology, Center for Materials Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Cuiping Zeng
- Key Laboratory of Quantitative Synthetic Biology, Center for Materials Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Xiang Gao
- Key Laboratory of Quantitative Synthetic Biology, Center for Materials Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Bo Wang
- Key Laboratory of Quantitative Synthetic Biology, Center for Materials Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Chao Zhong
- Key Laboratory of Quantitative Synthetic Biology, Center for Materials Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
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26
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Kumar S, Padinhateeri R, Thakur S. Shear flow as a tool to distinguish microscopic activities of molecular machines in a chromatin loop. SOFT MATTER 2024; 20:6500-6506. [PMID: 39099470 DOI: 10.1039/d4sm00636d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/06/2024]
Abstract
Several types of molecular machines move along biopolymers like chromatin. However, the details about the microscopic activity of these machines and how to distinguish their modes of action are not well understood. We propose that the activity of such machines can be classified by studying looped chromatin under shear flow. Our simulations show that a chromatin-like polymer with two types of activities-constant (type-I) or local curvature-dependent tangential forces (type-II)-exhibits very different behavior under shear flow. We show that one can distinguish both activities by measuring the nature of a globule-to-extended coil transition, tank treading, and tumbling dynamics.
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Affiliation(s)
- Sandeep Kumar
- Department of Physics, Indian Institute of Science Education and Research Bhopal, Bhopal 462066, India.
| | - Ranjith Padinhateeri
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India.
| | - Snigdha Thakur
- Department of Physics, Indian Institute of Science Education and Research Bhopal, Bhopal 462066, India.
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27
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Dard A, Van Breusegem F, Mhamdi A. Redox regulation of gene expression: proteomics reveals multiple previously undescribed redox-sensitive cysteines in transcription complexes and chromatin modifiers. JOURNAL OF EXPERIMENTAL BOTANY 2024; 75:4476-4493. [PMID: 38642390 DOI: 10.1093/jxb/erae177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 04/17/2024] [Indexed: 04/22/2024]
Abstract
Redox signalling is crucial for regulating plant development and adaptation to environmental changes. Proteins with redox-sensitive cysteines can sense oxidative stress and modulate their functions. Recent proteomics efforts have comprehensively mapped the proteins targeted by oxidative modifications. The nucleus, the epicentre of transcriptional reprogramming, contains a large number of proteins that control gene expression. Specific redox-sensitive transcription factors have long been recognized as key players in decoding redox signals in the nucleus and thus in regulating transcriptional responses. Consequently, the redox regulation of the nuclear transcription machinery and its cofactors has received less attention. In this review, we screened proteomic datasets for redox-sensitive cysteines on proteins of the core transcription complexes and chromatin modifiers in Arabidopsis thaliana. Our analysis indicates that redox regulation affects every step of gene transcription, from initiation to elongation and termination. We report previously undescribed redox-sensitive subunits in transcription complexes and discuss the emerging challenges in unravelling the landscape of redox-regulated processes involved in nuclear gene transcription.
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Affiliation(s)
- Avilien Dard
- Department of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Gent, Belgium
- Center for Plant Systems Biology, VIB, 9052 Gent, Belgium
| | - Frank Van Breusegem
- Department of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Gent, Belgium
- Center for Plant Systems Biology, VIB, 9052 Gent, Belgium
| | - Amna Mhamdi
- Department of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Gent, Belgium
- Center for Plant Systems Biology, VIB, 9052 Gent, Belgium
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28
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He T, Xiao L, Qiao Y, Klingbeil O, Young E, Wu XS, Mannan R, Mahapatra S, Redin E, Cho H, Bao Y, Kandarpa M, Ching-Yi Tien J, Wang X, Eyunni S, Zheng Y, Kim N, Zheng H, Hou S, Su F, Miner SJ, Mehra R, Cao X, Abbineni C, Samajdar S, Ramachandra M, Dhanasekaran SM, Talpaz M, Parolia A, Rudin CM, Vakoc CR, Chinnaiyan AM. Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies. Cancer Cell 2024; 42:1336-1351.e9. [PMID: 39029462 DOI: 10.1016/j.ccell.2024.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 04/19/2024] [Accepted: 06/11/2024] [Indexed: 07/21/2024]
Abstract
The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.
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Affiliation(s)
- Tongchen He
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Lanbo Xiao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Yuanyuan Qiao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Olaf Klingbeil
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Eleanor Young
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Xiaoli S Wu
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Rahul Mannan
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Somnath Mahapatra
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Esther Redin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Hanbyul Cho
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yi Bao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Malathi Kandarpa
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jean Ching-Yi Tien
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Xiaoju Wang
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Sanjana Eyunni
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yang Zheng
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - NamHoon Kim
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Heng Zheng
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Siyu Hou
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA
| | - Fengyun Su
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Stephanie J Miner
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rohit Mehra
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Xuhong Cao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | | | | | | | - Saravana M Dhanasekaran
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Moshe Talpaz
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Abhijit Parolia
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Charles M Rudin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine Graduate School of Medicine Sciences, New York, NY 10065, USA
| | | | - Arul M Chinnaiyan
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA.
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29
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Zhang H, Gu Z, Zeng Y, Zhang Y. Mechanism of heterochromatin remodeling revealed by the DDM1 bound nucleosome structures. Structure 2024; 32:1222-1230.e4. [PMID: 38870940 DOI: 10.1016/j.str.2024.05.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 04/07/2024] [Accepted: 05/17/2024] [Indexed: 06/15/2024]
Abstract
The SWI/SNF2 chromatin remodeling factor decreased DNA methylation 1 (DDM1) is essential for the silencing of transposable elements (TEs) in both euchromatic and heterochromatic regions. Here, we determined the cryo-EM structures of DDM1-nucleosomeH2A and DDM1-nucleosomeH2A.W complexes at near-atomic resolution in the presence of the ATP analog ADP-BeFx. The structures show that nucleosomal DNA is unwrapped more on the surface of the histone octamer containing histone H2A than that containing histone H2A.W. DDM1 embraces one DNA gyre of the nucleosome and interacts with the N-terminal tails of histone H4. Although we did not observe DDM1-H2A.W interactions in our structures, the results of the pull-down experiments suggest a direct interaction between DDM1 and the core region of histone H2A.W. Our work provides mechanistic insights into the heterochromatin remodeling process driven by DDM1 in plants.
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Affiliation(s)
- Hongwei Zhang
- Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China.
| | - Zhanxi Gu
- Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuan Zeng
- Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China
| | - Yu Zhang
- Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China.
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30
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Aljahani A, Mauksch C, Oudelaar AM. The relationship between nucleosome positioning and higher-order genome folding. Curr Opin Cell Biol 2024; 89:102398. [PMID: 38991477 DOI: 10.1016/j.ceb.2024.102398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 05/23/2024] [Accepted: 06/18/2024] [Indexed: 07/13/2024]
Abstract
Eukaryotic genomes are organized into 3D structures, which range from small-scale nucleosome arrays to large-scale chromatin domains. These structures have an important role in the regulation of transcription and other nuclear processes. Despite advances in our understanding of the properties, functions, and underlying mechanisms of genome structures, there are many open questions about the interplay between these structures across scales. In particular, it is not well understood if and how 1D features of nucleosome arrays influence large-scale 3D genome folding patterns. In this review, we discuss recent studies that address these questions and summarize our current understanding of the relationship between nucleosome positioning and higher-order genome folding.
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Affiliation(s)
- Abrar Aljahani
- Max Planck Institute for Multidisciplinary Sciences, Genome Organization and Regulation, Göttingen, Germany; University of Göttingen, Göttingen, Germany
| | - Clemens Mauksch
- Max Planck Institute for Multidisciplinary Sciences, Genome Organization and Regulation, Göttingen, Germany; University of Göttingen, Göttingen, Germany
| | - A Marieke Oudelaar
- Max Planck Institute for Multidisciplinary Sciences, Genome Organization and Regulation, Göttingen, Germany.
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31
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Qian F, Zuo D, Xue Y, Guan W, Ullah N, Zhu J, Cai G, Zhu B, Wu X. Comprehensive genome-wide identification of Snf2 gene family and their expression profile under salt stress in six Brassica species of U's triangle model. PLANTA 2024; 260:49. [PMID: 38985323 DOI: 10.1007/s00425-024-04473-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/21/2024] [Indexed: 07/11/2024]
Abstract
MAIN CONCLUSION We comprehensively identified and analyzed the Snf2 gene family. Some Snf2 genes were involved in responding to salt stress based on the RNA-seq and qRT-PCR analysis. Sucrose nonfermenting 2 (Snf2) proteins are core components of chromatin remodeling complexes that not only alter DNA accessibility using the energy of ATP hydrolysis, but also play a critical regulatory role in growth, development, and stress response in eukaryotes. However, the comparative study of Snf2 gene family in the six Brassica species in U's triangle model remains unclear. Here, a total of 405 Snf2 genes were identified, comprising 53, 50, and 46 in the diploid progenitors: Brassica rapa (AA, 2n = 20), Brassica nigra (BB, 2n = 16), and Brassica oleracea (CC, 2n = 18), and 93, 91, and 72 in the allotetraploid: Brassica juncea (AABB, 2n = 36), Brassica napus (AACC, 2n = 38), and Brassica carinata (BBCC, 2n = 34), respectively. These genes were classified into six clades and further divided into 18 subfamilies based on their conserved motifs and domains. Intriguingly, these genes showed highly conserved chromosomal distributions and gene structures, indicating that few dynamic changes occurred during the polyploidization. The duplication modes of the six Brassica species were diverse, and the expansion of most Snf2 in Brassica occurred primarily through dispersed duplication (DSD) events. Additionally, the majority of Snf2 genes were under purifying selection during polyploidization, and some Snf2 genes were associated with various abiotic stresses. Both RNA-seq and qRT-PCR analysis showed that the expression of BnaSnf2 genes was significantly induced under salt stress, implying their involvement in salt tolerance response in Brassica species. The results provide a comprehensive understanding of the Snf2 genes in U's triangle model species, which will facilitate further functional analysis of the Snf2 genes in Brassica plants.
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Affiliation(s)
- Fang Qian
- Key Laboratory of Biology and Genetic Improvement of Oil Crops, Ministry of Agriculture and Rural Affairs, Oil Crops Research Institute of the Chinese Academy of Agricultural Sciences, Wuhan, 430062, People's Republic of China
| | - Dan Zuo
- School of Life Sciences, Guizhou Normal University, Guiyang, 550025, People's Republic of China
| | - Yujun Xue
- Key Laboratory of Biology and Genetic Improvement of Oil Crops, Ministry of Agriculture and Rural Affairs, Oil Crops Research Institute of the Chinese Academy of Agricultural Sciences, Wuhan, 430062, People's Republic of China
| | - Wenjie Guan
- Key Laboratory of Biology and Genetic Improvement of Oil Crops, Ministry of Agriculture and Rural Affairs, Oil Crops Research Institute of the Chinese Academy of Agricultural Sciences, Wuhan, 430062, People's Republic of China
| | - Naseeb Ullah
- Key Laboratory of Biology and Genetic Improvement of Oil Crops, Ministry of Agriculture and Rural Affairs, Oil Crops Research Institute of the Chinese Academy of Agricultural Sciences, Wuhan, 430062, People's Republic of China
| | - Jiarong Zhu
- Key Laboratory of Biology and Genetic Improvement of Oil Crops, Ministry of Agriculture and Rural Affairs, Oil Crops Research Institute of the Chinese Academy of Agricultural Sciences, Wuhan, 430062, People's Republic of China
| | - Guangqin Cai
- Key Laboratory of Biology and Genetic Improvement of Oil Crops, Ministry of Agriculture and Rural Affairs, Oil Crops Research Institute of the Chinese Academy of Agricultural Sciences, Wuhan, 430062, People's Republic of China
| | - Bin Zhu
- School of Life Sciences, Guizhou Normal University, Guiyang, 550025, People's Republic of China.
| | - Xiaoming Wu
- Key Laboratory of Biology and Genetic Improvement of Oil Crops, Ministry of Agriculture and Rural Affairs, Oil Crops Research Institute of the Chinese Academy of Agricultural Sciences, Wuhan, 430062, People's Republic of China.
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32
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Cao Z, Wolynes PG. Motorized chain models of the ideal chromosome. Proc Natl Acad Sci U S A 2024; 121:e2407077121. [PMID: 38954553 PMCID: PMC11252987 DOI: 10.1073/pnas.2407077121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 06/06/2024] [Indexed: 07/04/2024] Open
Abstract
An array of motor proteins consumes chemical energy in setting up the architectures of chromosomes. Here, we explore how the structure of ideal polymer chains is influenced by two classes of motors. The first class which we call "swimming motors" acts to propel the chromatin fiber through three-dimensional space. They represent a caricature of motors such as RNA polymerases. Previously, they have often been described by adding a persistent flow onto Brownian diffusion of the chain. The second class of motors, which we call "grappling motors" caricatures the loop extrusion processes in which segments of chromatin fibers some distance apart are brought together. We analyze these models using a self-consistent variational phonon approximation to a many-body Master equation incorporating motor activities. We show that whether the swimming motors lead to contraction or expansion depends on the susceptibility of the motors, that is, how their activity depends on the forces they must exert. Grappling motors in contrast to swimming motors lead to long-ranged correlations that resemble those first suggested for fractal globules and that are consistent with the effective interactions inferred by energy landscape analyses of Hi-C data on the interphase chromosome.
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Affiliation(s)
- Zhiyu Cao
- Center for Theoretical Biological Physics, Rice University, Houston, TX77005
- Department of Chemical Physics, University of Science and Technology of China, Hefei, Anhui230026, China
| | - Peter G. Wolynes
- Center for Theoretical Biological Physics, Rice University, Houston, TX77005
- Department of Chemistry, Rice University, Houston, TX77005
- Department of Physics, Rice University, Houston, TX77005
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33
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Manivannan V, Inamdar MM, Padinhateeri R. Role of diffusion and reaction of the constituents in spreading of histone modification marks. PLoS Comput Biol 2024; 20:e1012235. [PMID: 38991050 PMCID: PMC11265668 DOI: 10.1371/journal.pcbi.1012235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 07/23/2024] [Accepted: 06/06/2024] [Indexed: 07/13/2024] Open
Abstract
Cells switch genes ON or OFF by altering the state of chromatin via histone modifications at specific regulatory locations along the chromatin polymer. These gene regulation processes are carried out by a network of reactions in which the histone marks spread to neighboring regions with the help of enzymes. In the literature, this spreading has been studied as a purely kinetic, non-diffusive process considering the interactions between neighboring nucleosomes. In this work, we go beyond this framework and study the spreading of modifications using a reaction-diffusion (RD) model accounting for the diffusion of the constituents. We quantitatively segregate the modification profiles generated from kinetic and RD models. The diffusion and degradation of enzymes set a natural length scale for limiting the domain size of modification spreading, and the resulting enzyme limitation is inherent in our model. We also demonstrate the emergence of confined modification domains without the explicit requirement of a nucleation site. We explore polymer compaction effects on spreading and show that single-cell domains may differ from averaged profiles. We find that the modification profiles from our model are comparable with existing H3K9me3 data of S. pombe.
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Affiliation(s)
- Vinoth Manivannan
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
| | - Mandar M. Inamdar
- Department of Civil Engineering, Indian Institute of Technology Bombay, Mumbai, India
| | - Ranjith Padinhateeri
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
- Sunita Sanghi Centre of Aging and Neurodegenerative Diseases, Indian Institute of Technology Bombay, Mumbai, India
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34
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Fendler NL, Ly J, Welp L, Urlaub H, Vos SM. Identification and characterization of a human MORC2 DNA binding region that is required for gene silencing. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.05.597643. [PMID: 38895295 PMCID: PMC11185635 DOI: 10.1101/2024.06.05.597643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
The eukaryotic microrchidia (MORC) protein family are DNA gyrase, Hsp90, histidine kinase, MutL (GHKL)-type ATPases involved in gene expression regulation and chromatin compaction. The molecular mechanisms underlying these activities are incompletely understood. Here we studied the full-length human MORC2 protein biochemically. We identified a DNA binding site in the C-terminus of the protein, and we observe that this region is heavily phosphorylated in cells. Phosphorylation of MORC2 reduces its affinity for DNA and appears to exclude the protein from the nucleus. We observe that DNA binding by MORC2 reduces its ATPase activity and that MORC2 can topologically entrap multiple DNA substrates between its N-terminal GHKL and C-terminal coiled coil 3 dimerization domains. Finally, we observe that the MORC2 C-terminal DNA binding region is required for gene silencing in cells. Together, our data provide a model to understand how MORC2 engages with DNA substrates to mediate gene silencing.
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Affiliation(s)
- Nikole L. Fendler
- Department of Biology, Massachusetts Institute of Technology, Building 68, 31 Ames St., Cambridge, MA 02139
| | - Jimmy Ly
- Department of Biology, Massachusetts Institute of Technology, Building 68, 31 Ames St., Cambridge, MA 02139
- Whitehead Institute for Biomedical Research, Cambridge, MA 02139
| | - Luisa Welp
- Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
- Bioanalytics Group, University Medical Center Göttingen, Department of Clinical Chemistry, Göttingen, Germany
| | - Henning Urlaub
- Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
- Bioanalytics Group, University Medical Center Göttingen, Department of Clinical Chemistry, Göttingen, Germany
| | - Seychelle M. Vos
- Department of Biology, Massachusetts Institute of Technology, Building 68, 31 Ames St., Cambridge, MA 02139
- Howard Hughes Medical Institute
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35
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He T, Xiao L, Qiao Y, Klingbeil O, Young E, Wu XS, Mannan R, Mahapatra S, Eyunni S, Ching-Yi Tien J, Wang X, Zheng Y, Kim N, Zheng H, Hou S, Su F, Miner SJ, Mehra R, Cao X, Abbineni C, Samajdar S, Ramachandra M, Parolia A, Vakoc CR, Chinnaiyan AM. Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.22.576669. [PMID: 38328238 PMCID: PMC10849552 DOI: 10.1101/2024.01.22.576669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells. A novel, orally bioavailable mSWI/SNF ATPase PROTAC degrader, AU-24118, demonstrated preferential efficacy in the SCLC-P relative to the SCLC-A subtype and significantly decreased tumor growth in preclinical models. AU-24118 did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F1/2 cofactor, POU2AF1 (OCA-B), were also remarkably sensitive to mSWI/SNF ATPase degradation. Mechanistically, mSWI/SNF ATPase degrader treatment in multiple myeloma cells compacted chromatin, dislodged POU2AF1 and IRF4, and decreased IRF4 signaling. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 enhanced survival compared to pomalidomide, an approved treatment for multiple myeloma. Taken together, our studies suggest that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.
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Affiliation(s)
- Tongchen He
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- These authors contributed equally
| | - Lanbo Xiao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- These authors contributed equally
| | - Yuanyuan Qiao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Olaf Klingbeil
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Eleanor Young
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Xiaoli S. Wu
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Rahul Mannan
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Somnath Mahapatra
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Sanjana Eyunni
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Jean Ching-Yi Tien
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Xiaoju Wang
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Yang Zheng
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - NamHoon Kim
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Heng Zheng
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Siyu Hou
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Fengyun Su
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Stephanie J. Miner
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Rohit Mehra
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Xuhong Cao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA
| | | | | | | | - Abhijit Parolia
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | | | - Arul M. Chinnaiyan
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
- Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Urology, University of Michigan, Ann Arbor, MI, USA
- Lead contact
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36
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Singha T, Li SF, Muthukumar M. Active dynamics of charged macromolecules. ARXIV 2024:arXiv:2405.13963v1. [PMID: 38827460 PMCID: PMC11142324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
We study the role of active coupling on the transport properties of homogeneously charged macromolecules in an infinitely dilute solution. An enzyme becomes actively bound to a segment of the macromolecule, exerting an electrostatic force on it. Eventually, thermal fluctuations cause it to become unbound, introducing active coupling into the system. We study the mean-squared displacement (MSD) and find a new scaling regime compared to the thermal counterpart in the presence of hydrodynamic and segment-segment electrostatic interactions. Furthermore, the study of segment-segment equal-time correlation reveals the swelling of the macromolecule. Further, we derive the concentration equation of the macromolecule with active binding and study how the cooperative diffusivity of the macromolecules get modified by its environment, including the macromolecules itself. It turns out that these active fluctuations enhance the effective diffusivity of the macromolecules. The derived closed-form expression for diffusion constant is pertinent to the accurate interpretation of light scattering data in multi-component systems with binding-unbinding equilibria.
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Affiliation(s)
- Tapas Singha
- Laboratoire Physique des Cellules et Cancer (PCC), Institut Curie, PSL Research University, CNRS UMR168, 75005 Paris, France
| | - Siao-Fong Li
- Department of Physics, University of Massachusetts, Amherst, Massachusetts 01003, USA
| | - Murugappan Muthukumar
- Department of Polymer Science and Engineering, University of Massachusetts, Amherst, Massachusetts 01003, USA
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Driesen J, Van Hoecke H, Maes L, Janssens S, Acke F, De Leenheer E. CHD7 Disorder-Not CHARGE Syndrome-Presenting as Isolated Cochleovestibular Dysfunction. Genes (Basel) 2024; 15:643. [PMID: 38790272 PMCID: PMC11120670 DOI: 10.3390/genes15050643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/03/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
CHARGE syndrome, characterized by a distinct set of clinical features, has been linked primarily to mutations in the CHD7 gene. Initially defined by specific clinical criteria, including coloboma, heart defects, choanal atresia, delayed growth, and ear anomalies, CHARGE syndrome's diagnostic spectrum has broadened since the identification of CHD7. Variants in this gene exhibit considerable phenotypic variability, leading to the adoption of the term "CHD7 disorder" to encompass a wider range of associated symptoms. Recent research has identified CHD7 variants in individuals with isolated features such as autism spectrum disorder or gonadotropin-releasing hormone deficiency. In this study, we present three cases from two different families exhibiting audiovestibular impairment as the primary manifestation of a CHD7 variant. We discuss the expanding phenotypic variability observed in CHD7-related disorders, highlighting the importance of considering CHD7 in nonsyndromic hearing loss cases, especially when accompanied by inner ear malformations on MRI. Additionally, we underscore the necessity of genetic counseling and comprehensive clinical evaluation for individuals with CHD7 variants to ensure appropriate management of associated health concerns.
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Affiliation(s)
- Jef Driesen
- Department of Head and Skin, Faculty of Medicine and Health Sciences, Ghent University Hospital, 9000 Ghent, Belgium
| | - Helen Van Hoecke
- Department of Head and Skin, Faculty of Medicine and Health Sciences, Ghent University Hospital, 9000 Ghent, Belgium
| | - Leen Maes
- Department of Rehabilitation Sciences, Faculty of Medicine and Health Sciences, Ghent University Hospital, 9000 Ghent, Belgium
| | - Sandra Janssens
- Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University Hospital, 9000 Ghent, Belgium
| | - Frederic Acke
- Department of Head and Skin, Faculty of Medicine and Health Sciences, Ghent University Hospital, 9000 Ghent, Belgium
| | - Els De Leenheer
- Department of Head and Skin, Faculty of Medicine and Health Sciences, Ghent University Hospital, 9000 Ghent, Belgium
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38
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Gourisankar S, Krokhotin A, Wenderski W, Crabtree GR. Context-specific functions of chromatin remodellers in development and disease. Nat Rev Genet 2024; 25:340-361. [PMID: 38001317 PMCID: PMC11867214 DOI: 10.1038/s41576-023-00666-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2023] [Indexed: 11/26/2023]
Abstract
Chromatin remodellers were once thought to be highly redundant and nonspecific in their actions. However, recent human genetic studies demonstrate remarkable biological specificity and dosage sensitivity of the thirty-two adenosine triphosphate (ATP)-dependent chromatin remodellers encoded in the human genome. Mutations in remodellers produce many human developmental disorders and cancers, motivating efforts to investigate their distinct functions in biologically relevant settings. Exquisitely specific biological functions seem to be an emergent property in mammals, and in many cases are based on the combinatorial assembly of subunits and the generation of stable, composite surfaces. Critical interactions between remodelling complex subunits, the nucleosome and other transcriptional regulators are now being defined from structural and biochemical studies. In addition, in vivo analyses of remodellers at relevant genetic loci have provided minute-by-minute insights into their dynamics. These studies are proposing new models for the determinants of remodeller localization and function on chromatin.
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Affiliation(s)
- Sai Gourisankar
- Department of Pathology, Stanford University, Stanford, CA, USA
- Department of Chemical Engineering, Stanford University, Stanford, CA, USA
| | - Andrey Krokhotin
- Department of Pathology, Stanford University, Stanford, CA, USA
- Department of Developmental Biology, Stanford University, Stanford, CA, USA
| | - Wendy Wenderski
- Department of Pathology, Stanford University, Stanford, CA, USA
- Department of Developmental Biology, Stanford University, Stanford, CA, USA
| | - Gerald R Crabtree
- Department of Pathology, Stanford University, Stanford, CA, USA.
- Department of Developmental Biology, Stanford University, Stanford, CA, USA.
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39
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He T, Cheng C, Qiao Y, Cho H, Young E, Mannan R, Mahapatra S, Miner SJ, Zheng Y, Kim N, Zeng VZ, Wisniewski JP, Hou S, Jackson B, Cao X, Su F, Wang R, Chang Y, Kuila B, Mukherjee S, Dukare S, Aithal KB, D.S. S, Abbineni C, Vaishampayan U, Lyssiotis CA, Parolia A, Xiao L, Chinnaiyan AM. Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer. Proc Natl Acad Sci U S A 2024; 121:e2322563121. [PMID: 38557192 PMCID: PMC11009648 DOI: 10.1073/pnas.2322563121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 03/02/2024] [Indexed: 04/04/2024] Open
Abstract
Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, an orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 (ATP binding cassette subfamily B member 1) overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.
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Affiliation(s)
- Tongchen He
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan410008, China
| | - Caleb Cheng
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Medical Scientist Training Program, University of Michigan, Ann Arbor, MI48109
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI48109
| | - Yuanyuan Qiao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI48109
| | - Hanbyul Cho
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
| | - Eleanor Young
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
| | - Rahul Mannan
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
| | - Somnath Mahapatra
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
| | - Stephanie J. Miner
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
| | - Yang Zheng
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
| | - NamHoon Kim
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
| | - Victoria Z. Zeng
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
| | - Jasmine P. Wisniewski
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
| | - Siyu Hou
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI48109
| | - Bailey Jackson
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
| | - Xuhong Cao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
- HHMI, University of Michigan, Ann Arbor, MI48109
| | - Fengyun Su
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
| | - Rui Wang
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
| | - Yu Chang
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
| | - Bilash Kuila
- Aurigene Oncology Limited, Bangalore, Karnataka560100, India
| | | | - Sandeep Dukare
- Aurigene Oncology Limited, Bangalore, Karnataka560100, India
| | - Kiran B. Aithal
- Aurigene Oncology Limited, Bangalore, Karnataka560100, India
| | - Samiulla D.S.
- Aurigene Oncology Limited, Bangalore, Karnataka560100, India
| | | | - Ulka Vaishampayan
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI48109
- Department of Internal Medicine, Division of Medical Oncology, University of Michigan, Ann Arbor, MI48109
| | - Costas A. Lyssiotis
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI48109
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI48109
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109
| | - Abhijit Parolia
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI48109
| | - Lanbo Xiao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI48109
| | - Arul M. Chinnaiyan
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI48109
- Department of Pathology, University of Michigan, Ann Arbor, MI48109
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI48109
- HHMI, University of Michigan, Ann Arbor, MI48109
- Department of Urology, University of Michigan, Ann Arbor, MI 48109
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40
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Zhang H, Li S, Zhou R, Dong T, Zhang X, Yu M, Lin J, Shi M, Geng E, Li J, Wang M, Huang L, Yang XP, Sun S. SRCAP complex promotes lung cancer progression by reprograming the oncogenic transcription of Hippo-YAP/TAZ signaling pathway. Cancer Lett 2024; 585:216667. [PMID: 38280479 DOI: 10.1016/j.canlet.2024.216667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 01/14/2024] [Accepted: 01/18/2024] [Indexed: 01/29/2024]
Abstract
The activation of YAP/TAZ, a pair of paralogs of transcriptional coactivators, initiates a dysregulated transcription program, which is a key feature of human cancer cells. However, it is not fully understood how YAP/TAZ promote dysregulated transcription for tumor progression. In this study, we employed the BioID method to identify the interactome of YAP/TAZ and discovered that YAP/TAZ interact with multiple components of SRCAP complex, a finding that was further validated through endogenous and exogenous co-immunoprecipitation, as well as immunofluorescence experiments. CUT&Tag analysis revealed that SRCAP complex facilitates the deposition of histone variant H2A.Z at target promoters. The depletion of SRCAP complex resulted in a decrease in H2A.Z occupancy and the oncogenic transcription of YAP/TAZ target genes. Additionally, the blockade of SRCAP complex suppressed YAP-driven tumor growth. In a genetically engineered lung adenocarcinoma mouse model and non-small cell lung cancer patients, SRCAP complex and H2A.Z deposition were found to be upregulated. This upregulation was statistically correlated with YAP expression, pathological stages, and poor survival in lung cancer patients. Together, our study uncovers that SRCAP complex plays a critical role in YAP/TAZ oncogenic transcription by coordinating H2A.Z deposition during cancer progression, providing potential targets for cancer diagnosis and prevention.
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Affiliation(s)
- Huixia Zhang
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China
| | - Shasha Li
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China
| | - Runxin Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China
| | - Tianqi Dong
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China
| | - Xiao Zhang
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China
| | - Man Yu
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China
| | - Jiaming Lin
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China
| | - Mingjun Shi
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China
| | - Ershuo Geng
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China
| | - Juebei Li
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China
| | - Mingwei Wang
- Department of Pathology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430079, China
| | - Liu Huang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Wuhan, 430030, China
| | - Xiang-Ping Yang
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China
| | - Shuguo Sun
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China; Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China.
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Zhang G, Jiao Y, Zhao Z, Chen Q, Wang Z, Zhu J, Lv N, Sun G. Genome-Wide and Expression Pattern Analysis of the HIT4 Gene Family Uncovers the Involvement of GHHIT4_4 in Response to Verticillium Wilt in Gossypium hirsutum. Genes (Basel) 2024; 15:348. [PMID: 38540407 PMCID: PMC10970331 DOI: 10.3390/genes15030348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 03/01/2024] [Accepted: 03/04/2024] [Indexed: 06/14/2024] Open
Abstract
Chromatin remodelers are essential for regulating plant growth, development, and responses to environmental stresses. HIT4 (HEAT-INTOLERANT 4) is a novel stress-induced chromatin remodeling factor that has been less studied in abiotic stress and stress resistance, particularly in cotton. In this study, we conducted a comprehensive analysis of the members of the HIT4 gene family in Gossypium hirsutum using bioinformatics methods, including phylogenetic relationships, gene organization, transcription profiles, phylogenetic connections, selection pressure, and stress response. A total of 18 HIT4 genes were identified in four cotton species, with six HIT4 gene members in upland cotton. Based on the evolutionary relationships shown in the phylogenetic tree, the 18 HIT4 protein sequences were classified into four distinct subgroups. Furthermore, we conducted chromosome mapping to determine the genomic locations of these genes and visually represented the structural characteristics of HIT4 in G. hirsutum. In addition, we predicted the regulatory elements in HIT4 in G. hirsutum and conducted an analysis of repetitive sequences and gene collinearity among HIT4 in four cotton species. Moreover, we calculated the Ka/Ks ratio for homologous genes to assess the selection pressure acting on HIT4. Using RNA-seq, we explored the expression patterns of HIT4 genes in G. hirsutum and Gossypium barbadense. Through weighted gene co-expression network analysis (WGCNA), we found that GHHIT4_4 belonged to the MEblue module, which was mainly enriched in pathways such as DNA replication, phagosome, pentose and glucuronate interconversions, steroid biosynthesis, and starch and sucrose metabolism. This module may regulate the mechanism of upland cotton resistance to Verticillium wilt through DNA replication, phagosome, and various metabolic pathways. In addition, we performed heterologous overexpression of GH_D11G0591 (GHHIT4_4) in tobacco, and the results showed a significant reduction in disease index compared to the wild type, with higher expression levels of disease resistance genes in the transgenic tobacco. After conducting a VIGS (virus-induced gene silencing) experiment in cotton, the results indicated that silencing GHHIT4_4 had a significant impact, the resistance to Verticillium wilt weakened, and the internode length of the plants significantly decreased by 30.7% while the number of true leaves increased by 41.5%. qRT-PCR analysis indicated that GHHIT4_4 mainly enhanced cotton resistance to Verticillium wilt by indirectly regulating the PAL, 4CL, and CHI genes. The subcellular localization results revealed that GHHIT4_4 was predominantly distributed in the mitochondria and nucleus. This study offers preliminary evidence for the involvement of the GHHIT4_4 in cotton resistance to Verticillium wilt and lays the foundation for further research on the disease resistance mechanism of this gene in cotton.
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Affiliation(s)
- Guoli Zhang
- Biotechnology Research Institute, Xinjiang Academy of Agricultural and Reclamation, 221 Wuyi Highway, Shihezi 832000, China; (G.Z.)
- College of Agriculture, Xinjiang Agricultural University, 311 Nongda East Road, Urumqi 830052, China; (Y.J.)
- Xinjiang Production and Construction Group Key Laboratory of Crop Germplasm Enhancement and Gene Resources Utilization, Shehezi 832000, China
| | - Yang Jiao
- College of Agriculture, Xinjiang Agricultural University, 311 Nongda East Road, Urumqi 830052, China; (Y.J.)
- Xinjiang Production and Construction Group Key Laboratory of Crop Germplasm Enhancement and Gene Resources Utilization, Shehezi 832000, China
- Xinjiang Academy of Agricultural and Reclamation, 221 Wuyi Highway, Shihezi 832000, China
| | - Zengqiang Zhao
- Xinjiang Production and Construction Group Key Laboratory of Crop Germplasm Enhancement and Gene Resources Utilization, Shehezi 832000, China
- Xinjiang Academy of Agricultural and Reclamation, 221 Wuyi Highway, Shihezi 832000, China
| | - Quanjia Chen
- College of Agriculture, Xinjiang Agricultural University, 311 Nongda East Road, Urumqi 830052, China; (Y.J.)
| | - Zhijun Wang
- Biotechnology Research Institute, Xinjiang Academy of Agricultural and Reclamation, 221 Wuyi Highway, Shihezi 832000, China; (G.Z.)
- Xinjiang Production and Construction Group Key Laboratory of Crop Germplasm Enhancement and Gene Resources Utilization, Shehezi 832000, China
| | - Jincheng Zhu
- Biotechnology Research Institute, Xinjiang Academy of Agricultural and Reclamation, 221 Wuyi Highway, Shihezi 832000, China; (G.Z.)
- Xinjiang Production and Construction Group Key Laboratory of Crop Germplasm Enhancement and Gene Resources Utilization, Shehezi 832000, China
| | - Ning Lv
- Xinjiang Academy of Agricultural and Reclamation, 221 Wuyi Highway, Shihezi 832000, China
| | - Guoqing Sun
- Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China
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He T, Cheng C, Qiao Y, Cho H, Young E, Mannan R, Mahapatra S, Miner SJ, Zheng Y, Kim N, Zeng VZ, Wisniewski JP, Hou S, Jackson B, Cao X, Su F, Wang R, Chang Y, Kuila B, Mukherjee S, Dukare S, Aithal KB, D.S. S, Abbineni C, Lyssiotis CA, Parolia A, Xiao L, Chinnaiyan AM. Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.29.582768. [PMID: 38464081 PMCID: PMC10925251 DOI: 10.1101/2024.02.29.582768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Mammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 (BRD4) and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.
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Affiliation(s)
- Tongchen He
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- These authors contributed equally
| | - Caleb Cheng
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA
- These authors contributed equally
| | - Yuanyuan Qiao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Hanbyul Cho
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Eleanor Young
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Rahul Mannan
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Somnath Mahapatra
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Stephanie J. Miner
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Yang Zheng
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - NamHoon Kim
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Victoria Z. Zeng
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Jasmine P. Wisniewski
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Siyu Hou
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Bailey Jackson
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Xuhong Cao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA
| | - Fengyun Su
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Rui Wang
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Yu Chang
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | | | | | | | | | | | | | - Costas A. Lyssiotis
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA
| | - Abhijit Parolia
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Lanbo Xiao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Arul M. Chinnaiyan
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
- Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Urology, University of Michigan, Ann Arbor, MI, USA
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Turkova T, Kokavec J, Zikmund T, Dibus N, Pimkova K, Nemec D, Holeckova M, Ruskova L, Sedlacek R, Cermak L, Stopka T. Differential requirements for Smarca5 expression during hematopoietic stem cell commitment. Commun Biol 2024; 7:244. [PMID: 38424235 PMCID: PMC10904812 DOI: 10.1038/s42003-024-05917-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 02/14/2024] [Indexed: 03/02/2024] Open
Abstract
The formation of hematopoietic cells relies on the chromatin remodeling activities of ISWI ATPase SMARCA5 (SNF2H) and its complexes. The Smarca5 null and conditional alleles have been used to study its functions in embryonic and organ development in mice. These mouse model phenotypes vary from embryonic lethality of constitutive knockout to less severe phenotypes observed in tissue-specific Smarca5 deletions, e.g., in the hematopoietic system. Here we show that, in a gene dosage-dependent manner, the hypomorphic allele of SMARCA5 (S5tg) can rescue not only the developmental arrest in hematopoiesis in the hCD2iCre model but also the lethal phenotypes associated with constitutive Smarca5 deletion or Vav1iCre-driven conditional knockout in hematopoietic progenitor cells. Interestingly, the latter model also provided evidence for the role of SMARCA5 expression level in hematopoietic stem cells, as the Vav1iCre S5tg animals accumulate stem and progenitor cells. Furthermore, their hematopoietic stem cells exhibited impaired lymphoid lineage entry and differentiation. This observation contrasts with the myeloid lineage which is developing without significant disturbances. Our findings indicate that animals with low expression of SMARCA5 exhibit normal embryonic development with altered lymphoid entry within the hematopoietic stem cell compartment.
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Grants
- 24-10435S, 24-10353S Grantová Agentura České Republiky (Grant Agency of the Czech Republic)
- NU21-08-00312, NU22-05-00374 Ministerstvo Zdravotnictví Ceské Republiky (Ministry of Health of the Czech Republic)
- LX22NPO5102, SVV 260637, UNCE/MED/016, COOPERATIO Ministerstvo Školství, Mládeže a Tělovýchovy (Ministry of Education, Youth and Sports)
- CZ.02.1.01/0.0/0.0/16_013/0001789, CZ.02.1.01/0.0/0.0/18_046/0015861 Ministerstvo Školství, Mládeže a Tělovýchovy (Ministry of Education, Youth and Sports)
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Affiliation(s)
- Tereza Turkova
- Hematology Laboratories, BIOCEV; 1st Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Juraj Kokavec
- Hematology Laboratories, BIOCEV; 1st Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Tomas Zikmund
- Hematology Laboratories, BIOCEV; 1st Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Nikol Dibus
- Laboratory of Cancer Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Kristyna Pimkova
- Hematology Laboratories, BIOCEV; 1st Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Dusan Nemec
- Hematology Laboratories, BIOCEV; 1st Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Marketa Holeckova
- Hematology Laboratories, BIOCEV; 1st Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Livia Ruskova
- Hematology Laboratories, BIOCEV; 1st Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Radislav Sedlacek
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic
| | - Lukas Cermak
- Laboratory of Cancer Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
| | - Tomas Stopka
- Hematology Laboratories, BIOCEV; 1st Faculty of Medicine, Charles University, Vestec, Czech Republic.
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Aoki K, Hyuga M, Tarumoto Y, Nishibuchi G, Ueda A, Ochi Y, Sugino S, Mikami T, Kobushi H, Kato I, Akahane K, Inukai T, Takaori-Kondo A, Takita J, Ogawa S, Yusa K. Canonical BAF complex regulates the oncogenic program in human T-cell acute lymphoblastic leukemia. Blood 2024; 143:604-618. [PMID: 37922452 DOI: 10.1182/blood.2023020857] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 10/19/2023] [Accepted: 10/20/2023] [Indexed: 11/05/2023] Open
Abstract
ABSTRACT Acute leukemia cells require bone marrow microenvironments, known as niches, which provide leukemic cells with niche factors that are essential for leukemic cell survival and/or proliferation. However, it remains unclear how the dynamics of the leukemic cell-niche interaction are regulated. Using a genome-wide CRISPR screen, we discovered that canonical BRG1/BRM-associated factor (cBAF), a variant of the switch/sucrose nonfermenting chromatin remodeling complex, regulates the migratory response of human T-cell acute lymphoblastic leukemia (T-ALL) cells to a niche factor CXCL12. Mechanistically, cBAF maintains chromatin accessibility and allows RUNX1 to bind to CXCR4 enhancer regions. cBAF inhibition evicts RUNX1 from the genome, resulting in CXCR4 downregulation and impaired migration activity. In addition, cBAF maintains chromatin accessibility preferentially at RUNX1 binding sites, ensuring RUNX1 binding at these sites, and is required for expression of RUNX1-regulated genes, such as CDK6; therefore, cBAF inhibition negatively impacts cell proliferation and profoundly induces apoptosis. This anticancer effect was also confirmed using T-ALL xenograft models, suggesting cBAF as a promising therapeutic target. Thus, we provide novel evidence that cBAF regulates the RUNX1-driven leukemic program and governs migration activity toward CXCL12 and cell-autonomous growth in human T-ALL.
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Affiliation(s)
- Kazunari Aoki
- Stem Cell Genetics, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Mizuki Hyuga
- Stem Cell Genetics, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Tarumoto
- Stem Cell Genetics, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Gohei Nishibuchi
- Stem Cell Genetics, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Atsushi Ueda
- Stem Cell Genetics, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yotaro Ochi
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan
| | - Seiichi Sugino
- Stem Cell Genetics, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Takashi Mikami
- Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hirokazu Kobushi
- Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Itaru Kato
- Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koshi Akahane
- Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Takeshi Inukai
- Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Akifumi Takaori-Kondo
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Junko Takita
- Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan
- Department of Medicine, Centre for Haematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden
| | - Kosuke Yusa
- Stem Cell Genetics, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
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45
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Liu J, Ke M, Sun Y, Niu S, Zhang W, Li Y. Epigenetic regulation and epigenetic memory resetting during plant rejuvenation. JOURNAL OF EXPERIMENTAL BOTANY 2024; 75:733-745. [PMID: 37930766 DOI: 10.1093/jxb/erad435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 10/29/2023] [Indexed: 11/07/2023]
Abstract
Reversal of plant developmental status from the mature to the juvenile phase, thus leading to the restoration of the developmental potential, is referred to as plant rejuvenation. It involves multilayer regulation, including resetting gene expression patterns, chromatin remodeling, and histone modifications, eventually resulting in the restoration of juvenile characteristics. Although plants can be successfully rejuvenated using some forestry practices to restore juvenile morphology, physiology, and reproductive capabilities, studies on the epigenetic mechanisms underlying this process are in the nascent stage. This review provides an overview of the plant rejuvenation process and discusses the key epigenetic mechanisms involved in DNA methylation, histone modification, and chromatin remodeling in the process of rejuvenation, as well as the roles of small RNAs in this process. Additionally, we present new inquiries regarding the epigenetic regulation of plant rejuvenation, aiming to advance our understanding of rejuvenation in sexually and asexually propagated plants. Overall, we highlight the importance of epigenetic mechanisms in the regulation of plant rejuvenation, providing valuable insights into the complexity of this process.
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Affiliation(s)
- Jie Liu
- State Key Laboratory of Tree Genetics and Breeding, Engineering Technology Research Center of Black Locust of National Forestry and Grassland Administration, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, PR China
| | - Meng Ke
- State Key Laboratory of Tree Genetics and Breeding, Engineering Technology Research Center of Black Locust of National Forestry and Grassland Administration, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, PR China
| | - Yuhan Sun
- State Key Laboratory of Tree Genetics and Breeding, Engineering Technology Research Center of Black Locust of National Forestry and Grassland Administration, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, PR China
| | - Shihui Niu
- State Key Laboratory of Tree Genetics and Breeding, Engineering Technology Research Center of Black Locust of National Forestry and Grassland Administration, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, PR China
| | - Wenli Zhang
- State Key Laboratory for Crop Genetics and Germplasm Enhancement, Nanjing Agricultural University, No.1 Weigang, Nanjing, Jiangsu 210095, PR China
| | - Yun Li
- State Key Laboratory of Tree Genetics and Breeding, Engineering Technology Research Center of Black Locust of National Forestry and Grassland Administration, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, PR China
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Flipphi M, Harispe ML, Hamari Z, Kocsubé S, Scazzocchio C, Ramón A. An ascomycete H4 variant with an unknown function. ROYAL SOCIETY OPEN SCIENCE 2024; 11:231705. [PMID: 38384781 PMCID: PMC10878826 DOI: 10.1098/rsos.231705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/22/2024] [Indexed: 02/23/2024]
Abstract
Histone variants leading to altered nucleosome structure, dynamics and DNA accessibility occur frequently, albeit rarely for H4. We carried out a comprehensive in silico scrutiny of fungal genomes, which revealed the presence of a novel H4 variant (H4E) in the ascomycetes, throughout the Pezizomycotina, in basal species of the Taphrinomycotina and also in the Glomeromycota. The coding cognate genes show a specific intron/exon organization, different from H4 canonical genes. H4Es diverge from canonical H4s mainly in the N- and C-terminal extensions, showing marked differences in the distribution and number of Lys and Arg residues, which may result in novel post-translational modifications. In Aspergillus nidulans (Pezizomycotina, Eurotiomycetes) the H4E variant protein level is low in mycelia. However, the encoding gene is well expressed at 37°C under nitrogen starvation. H4E localizes to the nucleus and interacts with H3, but its absence or overexpression does not result in any detectable phenotype. Deletion of only one of the of the two canonical H4 genes results in a strikingly impaired growth phenotype, which indicates that H4E cannot replace this canonical histone. Thus, an H4 variant is present throughout a whole subphylum of the ascomycetes, but with hitherto no experimentally detectable function.
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Affiliation(s)
- Michel Flipphi
- Department of Biochemical Engineering, Faculty of Science and Technology, University of Debrecen, Debrecen, Hungary
| | - María Laura Harispe
- Instituto de Profesores Artigas, Consejo de Formación en Educación (CFE, ANEP), Uruguay
| | - Zsuzsanna Hamari
- Faculty of Science and Informatics, Department of Microbiology, University of Szeged, Szeged, Hungary
| | - Sándor Kocsubé
- Faculty of Science and Informatics, Department of Microbiology, University of Szeged, Szeged, Hungary
| | - Claudio Scazzocchio
- Department of Life Sciences, Imperial College London, London, UK
- CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Gif-sur-Yvette 91198, France
| | - Ana Ramón
- Dpto. de Biología Celular y Molecular, Facultad de Ciencias, Sección Bioquímica, UdelaR, Uruguay
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Montibus B, Ragheb R, Diamanti E, Dunn SJ, Reynolds N, Hendrich B. The Nucleosome Remodelling and Deacetylation complex coordinates the transcriptional response to lineage commitment in pluripotent cells. Biol Open 2024; 13:bio060101. [PMID: 38149716 PMCID: PMC10836651 DOI: 10.1242/bio.060101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 12/18/2023] [Indexed: 12/28/2023] Open
Abstract
As cells exit the pluripotent state and begin to commit to a specific lineage they must activate genes appropriate for that lineage while silencing genes associated with pluripotency and preventing activation of lineage-inappropriate genes. The Nucleosome Remodelling and Deacetylation (NuRD) complex is essential for pluripotent cells to successfully undergo lineage commitment. NuRD controls nucleosome density at regulatory sequences to facilitate transcriptional responses, and also has been shown to prevent unscheduled transcription (transcriptional noise) in undifferentiated pluripotent cells. How these activities combine to ensure cells engage a gene expression program suitable for successful lineage commitment has not been determined. Here, we show that NuRD is not required to silence all genes. Rather, it restricts expression of genes primed for activation upon exit from the pluripotent state, but maintains them in a transcriptionally permissive state in self-renewing conditions, which facilitates their subsequent activation upon exit from naïve pluripotency. We further show that NuRD coordinates gene expression changes, which acts to maintain a barrier between different stable states. Thus NuRD-mediated chromatin remodelling serves multiple functions, including reducing transcriptional noise, priming genes for activation and coordinating the transcriptional response to facilitate lineage commitment.
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Affiliation(s)
- Bertille Montibus
- Wellcome – MRC Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, United Kingdom
| | - Ramy Ragheb
- Wellcome – MRC Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, United Kingdom
| | - Evangelia Diamanti
- Wellcome – MRC Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge CB2 0AW, UK
| | - Sara-Jane Dunn
- Microsoft Research, 21 Station Road, Cambridge CB1 2FB, UK
| | - Nicola Reynolds
- Wellcome – MRC Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, United Kingdom
| | - Brian Hendrich
- Wellcome – MRC Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, United Kingdom
- Department of Biochemistry, University of Cambridge, Cambridge CB2 1QR, UK
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48
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Shirbhate E, Singh V, Jahoriya V, Mishra A, Veerasamy R, Tiwari AK, Rajak H. Dual inhibitors of HDAC and other epigenetic regulators: A novel strategy for cancer treatment. Eur J Med Chem 2024; 263:115938. [PMID: 37989059 DOI: 10.1016/j.ejmech.2023.115938] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 10/25/2023] [Accepted: 11/05/2023] [Indexed: 11/23/2023]
Abstract
A significant advancement in the field of epigenetic drug discovery has been evidenced in recent years. Epigenetic alterations are hereditary, nevertheless reversible variations to DNA or histone adaptations that regulate gene function individualistically of the fundamental sequence. The design and synthesis of various drugs targeting epigenetic regulators open a new door for epigenetic-targeted therapies to parade worthwhile therapeutic potential for haematological and solid malignancies. Several ongoing clinical trials on dual targeting strategy are being conducted comprising HDAC inhibitory component and an epigenetic regulating agent. In this perspective, the review discusses the pharmacological aspects of HDAC and other epigenetic regulating factors as dual inhibitors as an emerging alternative approach for combination therapies.
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Affiliation(s)
- Ekta Shirbhate
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, 495 009, CG, India
| | - Vaibhav Singh
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, 495 009, CG, India
| | - Varsha Jahoriya
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, 495 009, CG, India
| | - Aditya Mishra
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, 495 009, CG, India
| | - Ravichandran Veerasamy
- Faculty of Pharmacy, AIMST University, Semeling, 08100, Bedong, Kedah Darul Aman, Malaysia
| | - Amit K Tiwari
- Cancer & System Therapeutics, UAMS College of Pharmacy, UAMS - University of Arkansas for Medical Sciences, AR, United States
| | - Harish Rajak
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, 495 009, CG, India.
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Hernández-Oliveras A, Zarain-Herzberg A. The role of Ca 2+-signaling in the regulation of epigenetic mechanisms. Cell Calcium 2024; 117:102836. [PMID: 37988873 DOI: 10.1016/j.ceca.2023.102836] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 11/10/2023] [Accepted: 11/16/2023] [Indexed: 11/23/2023]
Abstract
Epigenetic mechanisms regulate multiple cell functions like gene expression and chromatin conformation and stability, and its misregulation could lead to several diseases including cancer. Epigenetic drugs are currently under investigation in a broad range of diseases, but the cellular processes involved in regulating epigenetic mechanisms are not fully understood. Calcium (Ca2+) signaling regulates several cellular mechanisms such as proliferation, gene expression, and metabolism, among others. Moreover, Ca2+ signaling is also involved in diseases such as neurological disorders, cardiac, and cancer. Evidence indicates that Ca2+ signaling and epigenetics are involved in the same cellular functions, which suggests a possible interplay between both mechanisms. Ca2+-activated transcription factors regulate the recruitment of chromatin remodeling complexes into their target genes, and Ca2+-sensing proteins modulate their activity and intracellular localization. Thus, Ca2+ signaling is an important regulator of epigenetic mechanisms. Moreover, Ca2+ signaling activates epigenetic mechanisms that in turn regulate genes involved in Ca2+ signaling, suggesting possible feedback between both mechanisms. The understanding of how epigenetics are regulated could lead to developing better therapeutical approaches.
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Affiliation(s)
- Andrés Hernández-Oliveras
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Angel Zarain-Herzberg
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico.
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50
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Xiao M, Kondo S, Nomura M, Kato S, Nishimura K, Zang W, Zhang Y, Akashi T, Viny A, Shigehiro T, Ikawa T, Yamazaki H, Fukumoto M, Tanaka A, Hayashi Y, Koike Y, Aoyama Y, Ito H, Nishikawa H, Kitamura T, Kanai A, Yokoyama A, Fujiwara T, Goyama S, Noguchi H, Lee SC, Toyoda A, Hinohara K, Abdel-Wahab O, Inoue D. BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state. Nat Commun 2023; 14:8372. [PMID: 38102116 PMCID: PMC10724271 DOI: 10.1038/s41467-023-44081-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 11/29/2023] [Indexed: 12/17/2023] Open
Abstract
ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.
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Affiliation(s)
- Muran Xiao
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
- Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Shinji Kondo
- Center for Genome Informatics, Joint Support-Center for Data Science Research, Research Organization of Information and Systems, National Institute of Genetics, Mishima, Japan
- Advanced Genomics Center, National Institute of Genetics, Mishima, Japan
| | - Masaki Nomura
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
- Facility for iPS Cell Therapy, CiRA Foundation, Kyoto, Japan
| | - Shinichiro Kato
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Institute for Advanced Study, Nagoya University, Nagoya, Japan
- Center for 5D Cell Dynamics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Koutarou Nishimura
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
| | - Weijia Zang
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yifan Zhang
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomohiro Akashi
- Center for 5D Cell Dynamics, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Division of Systems Biology, Center for Neurological Diseases and Cancer, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Aaron Viny
- Department of Medicine, Division of Hematology and Oncology, and Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA
| | - Tsukasa Shigehiro
- Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan
| | - Tomokatsu Ikawa
- Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan
| | - Hiromi Yamazaki
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
| | - Miki Fukumoto
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
| | - Atsushi Tanaka
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
- Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yasutaka Hayashi
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
| | - Yui Koike
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
| | - Yumi Aoyama
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiromi Ito
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
| | - Hiroyoshi Nishikawa
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Institute for Advanced Study, Nagoya University, Nagoya, Japan
- Center for 5D Cell Dynamics, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo/Chiba, Japan
| | - Toshio Kitamura
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan
- Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Akinori Kanai
- Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Akihiko Yokoyama
- Tsuruoka Metabolomics Laboratory, National Cancer Center, Yamagata, Japan
| | - Tohru Fujiwara
- Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Laboratory Diagnostics, Tohoku University Hospital, Sendai, Japan
| | - Susumu Goyama
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Hideki Noguchi
- Center for Genome Informatics, Joint Support-Center for Data Science Research, Research Organization of Information and Systems, National Institute of Genetics, Mishima, Japan
- Advanced Genomics Center, National Institute of Genetics, Mishima, Japan
| | - Stanley C Lee
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
| | - Atsushi Toyoda
- Advanced Genomics Center, National Institute of Genetics, Mishima, Japan
- Comparative Genomics Laboratory, National Institute of Genetics, Mishima, Japan
| | - Kunihiko Hinohara
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Institute for Advanced Study, Nagoya University, Nagoya, Japan
- Center for 5D Cell Dynamics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Omar Abdel-Wahab
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Daichi Inoue
- Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan.
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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