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Daskeviciute D, Chappell-Maor L, Sainty B, Arnaud P, Iglesias-Platas I, Simon C, Okae H, Arima T, Vassena R, Lartey J, Monk D. Non-canonical imprinting, manifesting as post-fertilization placenta-specific parent-of-origin dependent methylation, is not conserved in humans. Hum Mol Genet 2025; 34:626-638. [PMID: 39825493 PMCID: PMC11924184 DOI: 10.1093/hmg/ddaf009] [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: 06/17/2024] [Revised: 12/19/2024] [Accepted: 01/14/2025] [Indexed: 01/20/2025] Open
Abstract
Genomic imprinting is the parent-of-origin dependent monoallelic expression of genes often associated with regions of germline-derived DNA methylation that are maintained as differentially methylated regions (gDMRs) in somatic tissues. This form of epigenetic regulation is highly conserved in mammals and is thought to have co-evolved with placentation. Tissue-specific gDMRs have been identified in human placenta, suggesting that species-specific imprinting dependent on unorthodox epigenetic establishment or maintenance may be more widespread than previously anticipated. Non-canonical imprinting, reliant on differential allelic H3K27me3 enrichment, has been reported in mouse and rat pre-implantation embryos, often overlapping long terminal repeat (LTR)-derived promoters. These non-canonical imprints lose parental allele-specific H3K27me3 specificity, subsequently gaining DNA methylation on the same allele in extra-embryonic tissues resulting in placenta-specific, somatically acquired maternal DMRs. To determine if similar non-canonical imprinting is present in the human placenta, we interrogated allelic DNA methylation for a selected number of loci, including (i) the human orthologues of non-canonical imprinted regions in mouse and rat, (ii) promoters of human LTR-derived transcripts, and (iii) CpG islands with intermediate placenta-specific methylation that are unmethylated in gametes and pre-implantation embryos. We failed to identify any non-canonical imprints in the human placenta whole villi samples. Furthermore, the assayed genes were shown to be biallelically expressed in human pre-implantation embryos, indicating they are not imprinted at earlier time points. Together, our work reiterates the continued evolution of placenta-specific imprinting in mammals, which we suggest is linked to epigenetic differences during the maternal-to-embryo transition and species-specific integration of retrotransposable elements.
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Affiliation(s)
- Dagne Daskeviciute
- Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich Research Park, Earlham Road, Norwich NR4 6PN, United Kingdom
| | - Louise Chappell-Maor
- Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich Research Park, Earlham Road, Norwich NR4 6PN, United Kingdom
| | - Becky Sainty
- Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich Research Park, Earlham Road, Norwich NR4 6PN, United Kingdom
| | - Philippe Arnaud
- Université Clermont Auvergne, CNRS, Inserm, GReD, 49 bd François Mitterrand, Clermont-Ferrand 63001, France
| | - Isabel Iglesias-Platas
- Institut de Recerca, Sant Joan de Déu, C. de Sta. Rosa, 39, Barcelona 08950, Spain
- Neonatal Research, Norwich and Norwich University Hospital NHS Foundation Trust, Colney Ln, Norwich NR4 7UY, United Kingdom
| | - Carlos Simon
- Carlos Simon Foundation, Rda. de Narcís Monturiol, 11, Bloque C, 46980 Paterna, Valencia, Spain
- Department of Obstetrics and Gynecology, Valencia University and INCLIVA, Av. Blasco Ibáñez 15, Valencia 46012, Spain
| | - Hiroaki Okae
- Department of Trophoblast Research, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
| | - Takahiro Arima
- Department of Informative Genetics, Environment and Genome Research Center, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Rita Vassena
- Fecundis, C/Baldoro i Reixac 10-12, Barcelona 08028, Spain
| | - Jon Lartey
- Department of Obstetrics and Gynaecology, Norwich and Norwich University Hospital NHS Foundation Trust, Colney Ln, Norwich NR4 7UY, United Kingdom
| | - David Monk
- Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich Research Park, Earlham Road, Norwich NR4 6PN, United Kingdom
- Bellvitge Biomedical Research Institute, Avinguda de la Granvia de l'Hospitalet 199, L'Hospitalet de Llobregat, Barcelona 08908, Spain
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2
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Shin JH, Yoo HB, Roe JS. Current advances and future directions in targeting histone demethylases for cancer therapy. Mol Cells 2025; 48:100192. [PMID: 39938867 PMCID: PMC11889978 DOI: 10.1016/j.mocell.2025.100192] [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: 12/13/2024] [Revised: 01/23/2025] [Accepted: 01/24/2025] [Indexed: 02/14/2025] Open
Abstract
Epigenetic regulators, known as "writers," erasers," and "readers," are essential for controlling gene expression by adding, removing, or recognizing post-translational modifications to histone tails, respectively. These regulators significantly affect genes involved in cancer initiation and maintenance. Recently, several clinical strategies targeting these epigenetic enzymes have emerged and some trials have demonstrated promising results for cancer treatment. Histone lysine demethylases (KDMs) yield distinct transcriptional outcomes that depend on the position of the methylated lysine and the specific genotype or lineage of the cancer cells. Due to their diverse roles in transcription, KDMs offer valuable opportunities for precision oncology, allowing treatments to be tailored to meet individual patient needs. This review emphasizes our current understanding of the functional relationship between KDMs and cancer as well as the development and application of small-molecule compounds that target KDMs.
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Affiliation(s)
- June-Ha Shin
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Hye-Been Yoo
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Jae-Seok Roe
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
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3
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Hong Y, Wang Y, Hao Z, Zhang X, Si Y, Lin G, Zhang S, Niu MM, Yang X, Zhang Y. Discovery of highly potent and novel LSD1 inhibitors for the treatment of acute myeloid leukemia: structure-based virtual screening, molecular dynamics simulation, and biological evaluation. Front Pharmacol 2025; 16:1510319. [PMID: 40083377 PMCID: PMC11903733 DOI: 10.3389/fphar.2025.1510319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 02/03/2025] [Indexed: 03/16/2025] Open
Abstract
Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy with a significant unmet clinical need for new therapeutic agents. Lysine-specific demethylase 1 (LSD1), a key regulator of leukemia stem cell self-renewal, has emerged as a promising epigenetic target for AML treatment. Herein, we employed an innovative multi-step integrated screening protocol, encompassing pharmacophore modeling, docking screening, molecular dynamics simulation, and biological evaluation, to identify novel LSD1 inhibitors. This comprehensive approach led to the discovery of six potent LSD1 inhibitors (we named these inhibitors LTMs 1-6), with LTM-1 exhibiting the most pronounced inhibitory effects on LSD1 (IC50 = 2.11 ± 0.14 nM) and the highest selectivity for LSD1 over LSD2 (>2370-fold). Notably, LTM-1 demonstrated outstanding antitumor activity both in vitro and in vivo. In vitro, LTM-1 showed potent anti-proliferative effects against LSD1-addicted MV-4-11 leukemia cells (IC50 = 0.16 ± 0.01 μM). In vivo, LTM-1 treatment significantly reduced tumor growth in MV-4-11 xenografted mice. Moreover, LTM-1 did not induce significant changes in liver and kidney function indices, suggesting a favorable safety profile. These results indicate that LTM-1 is a highly promising preclinical candidate for AML treatment, offering a new strategy for the development of more effective and selective LSD1 inhibitors.
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Affiliation(s)
- Ye Hong
- Department of Hematology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, China
- Department of Hematology, Binhai Couty People’s Hospital, Yancheng, Jiangsu, China
| | - Yuting Wang
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Ziyi Hao
- Department of Hematology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, China
| | - Xingxia Zhang
- Department of Hematology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, China
| | - Yejun Si
- Department of Hematology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, China
| | - Guoqiang Lin
- Department of Hematology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, China
| | - Shurong Zhang
- Department of Hematology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, China
| | - Miao-Miao Niu
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Xiaotian Yang
- Department of Hematology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, China
| | - Yanming Zhang
- Department of Hematology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, China
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4
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Kota SB, Kota SK. Lysine-specific demethylase 1a is obligatory for gene regulation during kidney development. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.25.640014. [PMID: 40060432 PMCID: PMC11888273 DOI: 10.1101/2025.02.25.640014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/14/2025]
Abstract
Histone methyltransferases and demethylases play crucial roles in gene regulation and are vital for proper functioning of multiple tissues. Lysine-specific histone demethylase 1A (Kdm1a), is responsible for the demethylation of specific lysines, namely K4 and K9, on histone H3. In this study, we investigated the functions of Kdm1a during mouse kidney development upon targeted deletion in renal progenitor cells. Loss of Kdm1a in Six2-positive nephron progenitors resulted in significant reduction in renal mass, tissue structural changes and impaired function. To further understand the molecular function of Kdm1a during kidney development, we conducted multi-omics analyses that included transcriptome profiling, Chromatin immunoprecipitation (ChIP) sequencing, and methylome assessments. These omic analyses identified Kdm1a as a critical gene regulator required for sustained expression of several nephron segment marker genes, as well as vast number of solute carrier (Slc) genes and a few imprinted genes. Absence of Kdm1a in kidneys led to an increase in global H3K9 methylation peaks, which correlated with the transcriptional downregulation of numerous genes. Among these were markers of nephron progenitors and presumptive tubular precursors. We also observed that specific gene bodies exhibited altered DNA methylation patterns at intragenic differentially methylated regions (DMRs) upon Kdm1a deletion, while the overall global levels of DNA methylation remained unchanged. Our data point to a key regulatory role for Kdm1a in the renal progenitor epigenome, influencing kidney specific gene expression in the developing nephrons. Together the study highlights an indispensable role for Kdm1a for proper development of mouse kidneys, and its absence leading to significant developmental and functional impairment.
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Affiliation(s)
- Savithri Balasubramanian Kota
- Nephrology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA; Current affiliation: Bayer U.S. LLC
| | - Satya K. Kota
- Division of Bone and Mineral Research, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, USA
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5
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Fanourgakis G, Gaspa-Toneu L, Komarov PA, Papasaikas P, Ozonov EA, Smallwood SA, Peters AHFM. DNA methylation modulates nucleosome retention in sperm and H3K4 methylation deposition in early mouse embryos. Nat Commun 2025; 16:465. [PMID: 39774947 PMCID: PMC11706963 DOI: 10.1038/s41467-024-55441-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 12/08/2024] [Indexed: 01/11/2025] Open
Abstract
In the germ line and during early embryogenesis, DNA methylation (DNAme) undergoes global erasure and re-establishment to support germ cell and embryonic development. While DNAme acquisition during male germ cell development is essential for setting genomic DNA methylation imprints, other intergenerational roles for paternal DNAme in defining embryonic chromatin are unknown. Through conditional gene deletion of the de novo DNA methyltransferases Dnmt3a and/or Dnmt3b, we observe that DNMT3A primarily safeguards against DNA hypomethylation in undifferentiated spermatogonia, while DNMT3B catalyzes de novo DNAme during spermatogonial differentiation. Failing de novo DNAme in Dnmt3a/Dnmt3b double deficient spermatogonia is associated with increased nucleosome occupancy in mature sperm, preferentially at sites with higher CpG content, supporting the model that DNAme modulates nucleosome retention in sperm. To assess the impact of altered sperm chromatin in formatting embryonic chromatin, we measure H3K4me3 occupancy at paternal and maternal alleles in 2-cell embryos using a transposon-based tagging approach. Our data show that reduced DNAme in sperm renders paternal alleles permissive for H3K4me3 establishment in early embryos, independently of possible paternal inheritance of sperm born H3K4me3. Together, this study provides evidence that paternally inherited DNAme directs chromatin formation during early embryonic development.
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Affiliation(s)
- Grigorios Fanourgakis
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland
| | - Laura Gaspa-Toneu
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland
- Faculty of Sciences, University of Basel, 4056, Basel, Switzerland
| | - Pavel A Komarov
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland
- Faculty of Sciences, University of Basel, 4056, Basel, Switzerland
| | - Panagiotis Papasaikas
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland
| | - Evgeniy A Ozonov
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland
| | - Sebastien A Smallwood
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland
| | - Antoine H F M Peters
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland.
- Faculty of Sciences, University of Basel, 4056, Basel, Switzerland.
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6
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Zhu S, Li J, Wang X, Jin Y, Wang H, An H, Sun H, Han L, Shen B, Wang Q. The chromatin accessibility landscape of mouse oocytes during configuration transition. Cell Prolif 2025; 58:e13733. [PMID: 39245646 PMCID: PMC11693577 DOI: 10.1111/cpr.13733] [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: 05/16/2024] [Revised: 07/15/2024] [Accepted: 07/30/2024] [Indexed: 09/10/2024] Open
Abstract
The transition of chromatin configuration in mammalian oocytes from a non-surrounded nucleolus (NSN) to a surrounded nucleolus (SN) is critical for acquiring the developmental competence. However, the genomic and epigenomic features underlying this process remain poorly understood. In the present study, we first establish the chromatin accessibility landscape of mouse oocytes from NSN to SN stage. Through the integrative analysis of multi-omics, we find that the establishment of DNA methylation in oocytes is independent of the dynamics of chromatin accessibility. In contrast, histone H3K4me3 status is closely associated with the dynamics of accessible regions during configuration transition. Furthermore, by focusing on the actively transcribed genes in NSN and SN oocytes, we discover that chromatin accessibility coupled with histone methylation (H3K4me3 and H3K27me3) participates in the transcriptional control during phase transition. In sum, our data provide a comprehensive resource for probing configuration transition in oocytes, and offer insights into the mechanisms determining chromatin dynamics and oocyte quality.
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Affiliation(s)
- Shuai Zhu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical CenterNanjing Medical UniversityNanjingChina
| | - Jiashuo Li
- State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical CenterNanjing Medical UniversityNanjingChina
| | - Xiuwan Wang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical CenterNanjing Medical UniversityNanjingChina
| | - Yifei Jin
- State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical CenterNanjing Medical UniversityNanjingChina
| | - Hengjie Wang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical CenterNanjing Medical UniversityNanjingChina
| | - Huiqing An
- State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical CenterNanjing Medical UniversityNanjingChina
| | - Hongzheng Sun
- State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical CenterNanjing Medical UniversityNanjingChina
| | - Longsen Han
- State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical CenterNanjing Medical UniversityNanjingChina
| | - Bin Shen
- State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical CenterNanjing Medical UniversityNanjingChina
| | - Qiang Wang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical CenterNanjing Medical UniversityNanjingChina
- Center for Global Health, School of Public HealthNanjing Medical UniversityNanjingChina
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7
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Wong KW, Zeng Y, Tay E, Teo JHJ, Cipta NO, Hamashima K, Yi Y, Liu H, Warrier T, Le MTN, Ng SC, Li QJ, Li H, Loh YH. Nuclear receptor-SINE B1 network modulates expanded pluripotency in blastoids and blastocysts. Nat Commun 2024; 15:10011. [PMID: 39562549 PMCID: PMC11577042 DOI: 10.1038/s41467-024-54381-0] [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: 10/08/2023] [Accepted: 11/04/2024] [Indexed: 11/21/2024] Open
Abstract
Embryonic stem cells possess the remarkable ability to self-organize into blastocyst-like structures upon induction. These stem cell-based embryo models serve as invaluable platforms for studying embryogenesis and therapeutic developments. Nevertheless, the specific intrinsic regulators that govern this potential for blastoid formation remain unknown. Here we demonstrate an intrinsic program that plays a crucial role in both blastoids and blastocysts across multiple species. We first establish metrics for grading the resemblance of blastoids to mouse blastocysts, and identify the differential activation of gene regulons involved in lineage specification among various blastoid grades. Notably, abrogation of nuclear receptor subfamily 1, group H, member 2 (Nr1h2) drastically reduces blastoid formation. Nr1h2 activation alone is sufficient to rewire conventional ESC into a distinct pluripotency state, enabling them to form blastoids with enhanced implantation capacity in the uterus and contribute to both embryonic and extraembryonic lineages in vivo. Through integrative multi-omics analyses, we uncover the broad regulatory role of Nr1h2 in the transcriptome, chromatin accessibility and epigenome, targeting genes associated with embryonic lineage and the transposable element SINE-B1. The Nr1h2-centred intrinsic program governs and drives the development of both blastoids and early embryos.
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Grants
- R03 OD038392 NIH HHS
- U19 AG074879 NIA NIH HHS
- P30 CA015083 NCI NIH HHS
- P30 DK084567 NIDDK NIH HHS
- P50 CA136393 NCI NIH HHS
- National Research Foundation, Singapore (NRF) Investigatorship award [NRFI2018- 02]; National Medical Research Council [NMRC/OFIRG21nov-0088]; Singapore Food Story (SFS) R&D Programme [W22W3D0007]; A*STAR Biomedical Research Council, Central Research Fund, Use-Inspired Basic Research (CRF UIBR); Competitive Research Programme (CRP) [NRF-CRP29-2022-0005]; Industry Alignment Fund - Prepositioning (IAF-PP) [H23J2a0095, H23J2a0097].
- NMRC grant MOH-000937-00 and A*STAR grant C210812003
- M.T.N.L. was supported by the Industry Alignment Fund - Prepositioning (IAF-PP) [H23J2a0097].
- H.L. was supported by grants from the Mayo Clinic Center for Biomedical Discovery, Center for Individualized Medicine, the Mayo Clinic Comprehensive Cancer Center (NIH; P30CA015083), the Mayo Clinic Center for Cell Signaling in Gastroenterology (NIH: P30DK084567), the Mayo Clinic Nutrition Obesity Research Program, the Glenn Foundation for Medical Research, the Eric & Wendy Schmidt Fund for AI Research & Innovation and the National Institutes of Health (NIH; U19AG74879, P50CA136393, R03OD038392).
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Affiliation(s)
- Ka Wai Wong
- Cell Fate Engineering and Therapeutics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Yingying Zeng
- Cell Fate Engineering and Therapeutics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore, Republic of Singapore
| | - Edison Tay
- Cell Fate Engineering and Therapeutics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Jia Hao Jackie Teo
- Cell Fate Engineering and Therapeutics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Nadia Omega Cipta
- Cell Fate Engineering and Therapeutics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Kiyofumi Hamashima
- Cell Fate Engineering and Therapeutics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Yao Yi
- Cell Fate Engineering and Therapeutics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Haijun Liu
- Endangered Species Conservation via Assisted Reproduction (ESCAR) Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Tushar Warrier
- Cell Fate Engineering and Therapeutics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Minh T N Le
- Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Soon Chye Ng
- Endangered Species Conservation via Assisted Reproduction (ESCAR) Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
- Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
- Sincere Healthcare Group, Singapore, Republic of Singapore
| | - Qi-Jing Li
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore, 138648, Republic of Singapore
| | - Hu Li
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Yuin-Han Loh
- Cell Fate Engineering and Therapeutics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore.
- Endangered Species Conservation via Assisted Reproduction (ESCAR) Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore.
- Department of Biological Sciences, National University of Singapore, Singapore, Republic of Singapore.
- NUS Graduate School's Integrative Sciences and Engineering Programme, National University of Singapore, Singapore, Republic of Singapore.
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
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8
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Cai W, Xiao C, Fan T, Deng Z, Wang D, Liu Y, Li C, He J. Targeting LSD1 in cancer: Molecular elucidation and recent advances. Cancer Lett 2024; 598:217093. [PMID: 38969160 DOI: 10.1016/j.canlet.2024.217093] [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: 05/09/2024] [Revised: 06/18/2024] [Accepted: 06/27/2024] [Indexed: 07/07/2024]
Abstract
Histones are the main components of chromatin, functioning as an instructive scaffold to maintain chromosome structure and regulate gene expression. The dysregulation of histone modification is associated with various pathological processes, especially cancer initiation and development, and histone methylation plays a critical role. However, the specific mechanisms and potential therapeutic targets of histone methylation in cancer are not elucidated. Lys-specific demethylase 1A (LSD1) was the first identified demethylase that specifically removes methyl groups from histone 3 at lysine 4 or lysine 9, acting as a repressor or activator of gene expression. Recent studies have shown that LSD1 promotes cancer progression in multiple epigenetic regulation or non-epigenetic manners. Notably, LSD1 dysfunction is correlated with repressive cancer immunity. Many LSD1 inhibitors have been developed and clinical trials are exploring their efficacy in monotherapy, or combined with other therapies. In this review, we summarize the oncogenic mechanisms of LSD1 and the current applications of LSD1 inhibitors. We highlight that LSD1 is a promising target for cancer treatment. This review will provide the latest theoretical references for further understanding the research progress of oncology and epigenetics, deepening the updated appreciation of epigenetics in cancer.
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Affiliation(s)
- Wenpeng Cai
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chu Xiao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tao Fan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ziqin Deng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Di Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yixiao Liu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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9
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Liu Y, Chen SJ, Ai C, Yu PX, Fang M, Wang H. Prenatal dexamethasone exposure impairs rat blood-testis barrier function and sperm quality in adult offspring via GR/KDM1B/FSTL3/TGFβ signaling. Acta Pharmacol Sin 2024; 45:1237-1251. [PMID: 38472317 PMCID: PMC11130295 DOI: 10.1038/s41401-024-01244-5] [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: 10/22/2023] [Accepted: 02/15/2024] [Indexed: 03/14/2024]
Abstract
Both epidemiological and animal studies suggest that adverse environment during pregnancy can change the offspring development programming, but it is difficult to achieve prenatal early warning. In this study we investigated the impact of prenatal dexamethasone exposure (PDE) on sperm quality and function of blood-testis barrier (BTB) in adult offspring and the underlying mechanisms. Pregnant rats were injected with dexamethasone (0.1, 0.2 and 0.4 mg·kg-1·d-1, s.c.) from GD9 to GD20. After weaning (PW4), the pups were fed with lab chow. At PW12 and PW28, the male offspring were euthanized to collect blood and testes samples. We showed that PDE significantly decreased sperm quality (including quantity and motility) in male offspring, which was associated with impaired BTB and decreased CX43/E-cadherin expression in the testis. We demonstrated that PDE induced morphological abnormalities of fetal testicle and Sertoli cell development originated from intrauterine. By tracing to fetal testicular Sertoli cells, we found that PDE dose-dependently increased expression of histone lysine demethylases (KDM1B), decreasing histone 3 lysine 9 dimethylation (H3K9me2) levels of follistatin-like-3 (FSTL3) promoter region and increased FSTL3 expression, and inhibited TGFβ signaling and CX43/E-cadherin expression in offspring before and after birth. These results were validated in TM4 Sertoli cells following dexamethasone treatment. Meanwhile, the H3K9me2 levels of FSTL3 promoter in maternal peripheral blood mononuclear cell (PBMC) and placenta were decreased and its expression increased, which was positively correlated with the changes in offspring testis. Based on analysis of human samples, we found that the H3K9me2 levels of FSTL3 promoter in maternal blood PBMC and placenta were positively correlated with fetal blood testosterone levels after prenatal dexamethasone exposure. We conclude that PDE can reduce sperm quality in adult offspring rats, which is related to the damage of testis BTB via epigenetic modification and change of FSTL3 expression in Sertoli cells. The H3K9me2 levels of the FSTL3 promoter and its expression in the maternal blood PBMC can be used as a prenatal warning marker for fetal testicular dysplasia.
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Affiliation(s)
- Yi Liu
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China
| | - Si-Jia Chen
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China
| | - Can Ai
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China
| | - Peng-Xia Yu
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China
| | - Man Fang
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China
| | - Hui Wang
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China.
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China.
- Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
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10
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Kim HM, Liu Z. LSD2 Is an Epigenetic Player in Multiple Types of Cancer and Beyond. Biomolecules 2024; 14:553. [PMID: 38785960 PMCID: PMC11118440 DOI: 10.3390/biom14050553] [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: 04/10/2024] [Revised: 04/27/2024] [Accepted: 04/30/2024] [Indexed: 05/25/2024] Open
Abstract
Histone demethylases, enzymes responsible for removing methyl groups from histone proteins, have emerged as critical players in regulating gene expression and chromatin dynamics, thereby influencing various cellular processes. LSD2 and LSD1 have attracted considerable interest among these demethylases because of their associations with cancer. However, while LSD1 has received significant attention, LSD2 has not been recognized to the same extent. In this study, we conduct a comprehensive comparison between LSD2 and LSD1, with a focus on exploring LSD2's implications. While both share structural similarities, LSD2 possesses unique features as well. Functionally, LSD2 shows diverse roles, particularly in cancer, with tissue-dependent roles. Additionally, LSD2 extends beyond histone demethylation, impacting DNA methylation, cancer cell reprogramming, E3 ubiquitin ligase activity and DNA damage repair pathways. This study underscores the distinct roles of LSD2, providing insights into their contributions to cancer and other cellular processes.
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Affiliation(s)
- Hyun-Min Kim
- Division of Natural and Applied Sciences, Duke Kunshan University, Kunshan 215316, China
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11
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Fang S, Chang KW, Lefebvre L. Roles of endogenous retroviral elements in the establishment and maintenance of imprinted gene expression. Front Cell Dev Biol 2024; 12:1369751. [PMID: 38505259 PMCID: PMC10948482 DOI: 10.3389/fcell.2024.1369751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 02/26/2024] [Indexed: 03/21/2024] Open
Abstract
DNA methylation (DNAme) has long been recognized as a host defense mechanism, both in the restriction modification systems of prokaryotes as well as in the transcriptional silencing of repetitive elements in mammals. When DNAme was shown to be implicated as a key epigenetic mechanism in the regulation of imprinted genes in mammals, a parallel with host defense mechanisms was drawn, suggesting perhaps a common evolutionary origin. Here we review recent work related to this hypothesis on two different aspects of the developmental imprinting cycle in mammals that has revealed unexpected roles for long terminal repeat (LTR) retroelements in imprinting, both canonical and noncanonical. These two different forms of genomic imprinting depend on different epigenetic marks inherited from the mature gametes, DNAme and histone H3 lysine 27 trimethylation (H3K27me3), respectively. DNAme establishment in the maternal germline is guided by transcription during oocyte growth. Specific families of LTRs, evading silencing mechanisms, have been implicated in this process for specific imprinted genes. In noncanonical imprinting, maternally inherited histone marks play transient roles in transcriptional silencing during preimplantation development. These marks are ultimately translated into DNAme, notably over LTR elements, for the maintenance of silencing of the maternal alleles in the extraembryonic trophoblast lineage. Therefore, LTR retroelements play important roles in both establishment and maintenance of different epigenetic pathways leading to imprinted expression during development. Because such elements are mobile and highly polymorphic among different species, they can be coopted for the evolution of new species-specific imprinted genes.
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Affiliation(s)
| | | | - Louis Lefebvre
- Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
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12
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Eggermann T. Human Reproduction and Disturbed Genomic Imprinting. Genes (Basel) 2024; 15:163. [PMID: 38397153 PMCID: PMC10888310 DOI: 10.3390/genes15020163] [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: 01/02/2024] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
Genomic imprinting is a specific mode of gene regulation which particularly accounts for the factors involved in development. Its disturbance affects the fetus, the course of pregnancy and even the health of the mother. In children, aberrant imprinting signatures are associated with imprinting disorders (ImpDis). These alterations also affect the function of the placenta, which has consequences for the course of the pregnancy. The molecular causes of ImpDis comprise changes at the DNA level and methylation disturbances (imprinting defects/ImpDefs), and there is an increasing number of reports of both pathogenic fetal and maternal DNA variants causing ImpDefs. These ImpDefs can be inherited, but prediction of the pregnancy complications caused is difficult, as they can cause miscarriages, aneuploidies, health issues for the mother and ImpDis in the child. Due to the complexity of imprinting regulation, each pregnancy or patient with suspected altered genomic imprinting requires a specific workup to identify the precise molecular cause and also careful clinical documentation. This review will cover the current knowledge on the molecular causes of aberrant imprinting signatures and illustrate the need to identify this basis as the prerequisite for personalized genetic and reproductive counselling of families.
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Affiliation(s)
- Thomas Eggermann
- Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH University Aachen, Pauwelsstr. 3, D-52074 Aachen, Germany
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13
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Liao J, Szabó PE. Role of transcription in imprint establishment in the male and female germ lines. Epigenomics 2024; 16:127-136. [PMID: 38126127 PMCID: PMC10825728 DOI: 10.2217/epi-2023-0344] [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: 10/02/2023] [Accepted: 11/27/2023] [Indexed: 12/23/2023] Open
Abstract
The authors highlight an area of research that focuses on the establishment of genomic imprints: how the female and male germlines set up opposite instructions for imprinted genes in the maternally and paternally inherited chromosomes. Mouse genetics studies have solidified the role of transcription across the germline differentially methylated regions in the establishment of maternal genomic imprinting. One work now reveals that such transcription is also important in paternal imprinting establishment. This allows the authors to propose a unifying mechanism, in the form of transcription across germline differentially methylated regions, that specifies DNA methylation imprint establishment. Differences in the timing, genomic location and nature of such transcription events in the male versus female germlines in turn explain the difference between paternal and maternal imprints.
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Affiliation(s)
- Ji Liao
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Piroska E Szabó
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
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14
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Sheikh KA, Iqubal A, Alam MM, Akhter M, Khan MA, Ehtaishamul Haque S, Parvez S, Jahangir U, Amir M, Khanna S, Shaquiquzzaman M. A Quinquennial Review of Potent LSD1 Inhibitors Explored for the Treatment of Different Cancers, with Special Focus on SAR Studies. Curr Med Chem 2024; 31:152-207. [PMID: 36718063 DOI: 10.2174/0929867330666230130093442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 09/30/2022] [Accepted: 11/17/2022] [Indexed: 02/01/2023]
Abstract
Cancer bears a significant share of global mortality. The enzyme Lysine Specific Demethylase 1 (LSD1, also known as KDM1A), since its discovery in 2004, has captured the attention of cancer researchers due to its overexpression in several cancers like acute myeloid leukaemia (AML), solid tumours, etc. The Lysine Specific Demethylase (LSD1) downregulation is reported to have an effect on cancer proliferation, migration, and invasion. Therefore, research to discover safer and more potent LSD1 inhibitors can pave the way for the development of better cancer therapeutics. These efforts have resulted in the synthesis of many types of derivatives containing diverse structural nuclei. The present manuscript describes the role of Lysine Specific Demethylase 1 (LSD1) in carcinogenesis, reviews the LSD1 inhibitors explored in the past five years and discusses their comprehensive structural activity characteristics apart from the thorough description of LSD1. Besides, the potential challenges, opportunities, and future perspectives in the development of LSD1 inhibitors are also discussed. The review suggests that tranylcypromine derivatives are the most promising potent LSD1 inhibitors, followed by triazole and pyrimidine derivatives with IC50 values in the nanomolar and sub-micromolar range. A number of potent LSD1 inhibitors derived from natural sources like resveratrol, protoberberine alkaloids, curcumin, etc. are also discussed. The structural-activity relationships discussed in the manuscript can be exploited to design potent and relatively safer LSD1 inhibitors as anticancer agents.
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Affiliation(s)
- Khursheed Ahmad Sheikh
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Ashif Iqubal
- Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Mohammad Mumtaz Alam
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Mymoona Akhter
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Mohammad Ahmed Khan
- Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Syed Ehtaishamul Haque
- Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Suhel Parvez
- Department of Toxicology, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Umar Jahangir
- Department of Amraaz-e-Jild wa Tazeeniyat, School of Unani Medical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Mohammad Amir
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Suruchi Khanna
- Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Mohammad Shaquiquzzaman
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
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15
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Terzi Çizmecioğlu N. Roles and Regulation of H3K4 Methylation During Mammalian Early Embryogenesis and Embryonic Stem Cell Differentiation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1470:73-96. [PMID: 38231346 DOI: 10.1007/5584_2023_794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
From generation of germ cells, fertilization, and throughout early mammalian embryonic development, the chromatin undergoes significant alterations to enable precise regulation of gene expression and genome use. Methylation of histone 3 lysine 4 (H3K4) correlates with active regions of the genome, and it has emerged as a dynamic mark throughout this timeline. The pattern and the level of H3K4 methylation are regulated by methyltransferases and demethylases. These enzymes, as well as their protein partners, play important roles in early embryonic development and show phenotypes in embryonic stem cell self-renewal and differentiation. The various roles of H3K4 methylation are interpreted by dedicated chromatin reader proteins, linking this modification to broader molecular and cellular phenotypes. In this review, we discuss the regulation of different levels of H3K4 methylation, their distinct accumulation pattern, and downstream molecular roles with an early embryogenesis perspective.
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16
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Aizawa E, Ozonov EA, Kawamura YK, Dumeau C, Nagaoka S, Kitajima TS, Saitou M, Peters AHFM, Wutz A. Epigenetic regulation limits competence of pluripotent stem cell-derived oocytes. EMBO J 2023; 42:e113955. [PMID: 37850882 PMCID: PMC10690455 DOI: 10.15252/embj.2023113955] [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: 03/07/2023] [Revised: 09/18/2023] [Accepted: 09/18/2023] [Indexed: 10/19/2023] Open
Abstract
Recent studies have reported the differentiation of pluripotent cells into oocytes in vitro. However, the developmental competence of in vitro-generated oocytes remains low. Here, we perform a comprehensive comparison of mouse germ cell development in vitro over all culture steps versus in vivo with the goal to understand mechanisms underlying poor oocyte quality. We show that the in vitro differentiation of primordial germ cells to growing oocytes and subsequent follicle growth is critical for competence for preimplantation development. Systematic transcriptome analysis of single oocytes that were subjected to different culture steps identifies genes that are normally upregulated during oocyte growth to be susceptible for misregulation during in vitro oogenesis. Many misregulated genes are Polycomb targets. Deregulation of Polycomb repression is therefore a key cause and the earliest defect known in in vitro oocyte differentiation. Conversely, structurally normal in vitro-derived oocytes fail at zygotic genome activation and show abnormal acquisition of 5-hydroxymethylcytosine on maternal chromosomes. Our data identify epigenetic regulation at an early stage of oogenesis limiting developmental competence and suggest opportunities for future improvements.
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Affiliation(s)
- Eishi Aizawa
- Institute of Molecular Health Sciences, Swiss Federal Institute of TechnologyETH ZurichZurichSwitzerland
- RIKEN Center for Biosystems Dynamics ResearchKobeJapan
| | - Evgeniy A Ozonov
- Friedrich Miescher Institute for Biomedical ResearchBaselSwitzerland
| | - Yumiko K Kawamura
- Friedrich Miescher Institute for Biomedical ResearchBaselSwitzerland
| | - Charles‐Etienne Dumeau
- Institute of Molecular Health Sciences, Swiss Federal Institute of TechnologyETH ZurichZurichSwitzerland
| | - So Nagaoka
- Department of EmbryologyNara Medical UniversityNaraJapan
| | | | - Mitinori Saitou
- Institute for the Advanced Study of Human Biology (ASHBi)Kyoto UniversityKyotoJapan
- Department of Anatomy and Cell Biology, Graduate School of MedicineKyoto UniversityKyotoJapan
- Center for iPS Cell Research and Application (CiRA)Kyoto UniversityKyotoJapan
| | - Antoine HFM Peters
- Friedrich Miescher Institute for Biomedical ResearchBaselSwitzerland
- Faculty of SciencesUniversity of BaselBaselSwitzerland
| | - Anton Wutz
- Institute of Molecular Health Sciences, Swiss Federal Institute of TechnologyETH ZurichZurichSwitzerland
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17
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Behluli L, Fontanilla AM, Andessner-Angleitner L, Tolar N, Molina JM, Gahurova L. Expression analysis suggests that DNMT3L is required for oocyte de novo DNA methylation only in Muridae and Cricetidae rodents. Epigenetics Chromatin 2023; 16:43. [PMID: 37924163 PMCID: PMC10625200 DOI: 10.1186/s13072-023-00518-2] [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: 08/23/2023] [Accepted: 10/25/2023] [Indexed: 11/06/2023] Open
Abstract
BACKGROUND During early mammalian development, DNA methylation undergoes two waves of reprogramming, enabling transitions between somatic cells, oocyte and embryo. The first wave of de novo DNA methylation establishment occurs in oocytes. Its molecular mechanisms have been studied in mouse, a classical mammalian model. Current model describes DNA methyltransferase 3A (DNMT3A) and its cofactor DNMT3L as two essential factors for oocyte DNA methylation-the ablation of either leads to nearly complete abrogation of DNA methylation. However, DNMT3L is not expressed in human oocytes, suggesting that the mechanism uncovered in mouse is not universal across mammals. RESULTS We analysed available RNA-seq data sets from oocytes of multiple mammals, including our novel data sets of several rodent species, and revealed that Dnmt3l is expressed only in the oocytes of mouse, rat and golden hamster, and at a low level in guinea pigs. We identified a specific promoter sequence recognised by an oocyte transcription factor complex associated with strong Dnmt3l activity and demonstrated that it emerged in the rodent clade Eumuroida, comprising the families Muridae (mice, rats, gerbils) and Cricetidae (hamsters). In addition, an evolutionarily novel promoter emerged in the guinea pig, driving weak Dnmt3l expression, likely without functional relevance. Therefore, Dnmt3l is expressed and consequently plays a role in oocyte de novo DNA methylation only in a small number of rodent species, instead of being an essential pan-mammalian factor. In contrast to somatic cells, where catalytically inactive DNMT3B interacts with DNMT3A, forming a heterotetramer, we did not find evidence for the expression of such inactive Dnmt3b isoforms in the oocytes of the tested species. CONCLUSIONS The analysis of RNA-seq data and genomic sequences revealed that DNMT3L is likely to play a role in oocytes de novo DNA methylation only in mice, rats, gerbils and hamsters. The mechanism governing de novo DNA methylation in the oocytes of most mammalian species, including humans, occurs through a yet unknown mechanism that differs from the current model discovered in mouse.
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Affiliation(s)
- Lirik Behluli
- Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia, Branisovska 1760, 37005, Ceske Budejovice, Czech Republic
| | - Alyssa M Fontanilla
- Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia, Branisovska 1760, 37005, Ceske Budejovice, Czech Republic
| | - Laura Andessner-Angleitner
- Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia, Branisovska 1760, 37005, Ceske Budejovice, Czech Republic
| | - Nikolas Tolar
- Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia, Branisovska 1760, 37005, Ceske Budejovice, Czech Republic
| | - Julia M Molina
- Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia, Branisovska 1760, 37005, Ceske Budejovice, Czech Republic
- Department of Biological Sciences, Faculty of Sciences and Languages, São Paulo State University "Júlio de Mesquita Filho" - UNESP, Assis, São Paulo, Brazil
| | - Lenka Gahurova
- Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia, Branisovska 1760, 37005, Ceske Budejovice, Czech Republic.
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18
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Xiong X, Yang M, Hai Z, Fei X, Zhu Y, Pan B, Yang Q, Xie Y, Cheng Y, Xiong Y, Lan D, Fu W, Li J. Maternal Kdm2a-mediated PI3K/Akt signaling and E-cadherin stimulate the morula-to-blastocyst transition revealing crucial roles in early embryonic development. Theriogenology 2023; 209:60-75. [PMID: 37356280 DOI: 10.1016/j.theriogenology.2023.06.017] [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: 04/10/2023] [Revised: 06/12/2023] [Accepted: 06/12/2023] [Indexed: 06/27/2023]
Abstract
Histone methylation plays an essential role in oocyte growth and preimplantation embryonic development. The modification relies on histone methyl-transferases and demethylases, and one of these, lysine-specific demethylase 2a (Kdm2a), is responsible for modulating histone methylation during oocyte and early embryonic development. The mechanism of how Kdm2a deficiency disrupts early embryonic development and fertility remains elusive. To determine if maternally deposited Kdm2a is required for preimplantation embryonic development, the expression profile of Kdm2a during early embryos was detected via immunofluorescence staining and RT-qPCR. The Kdm2a gene in oocytes was specifically deleted with the Zp3-Cre/LoxP system and the effects of maternal Kdm2a loss were studied through a comprehensive range of female reproductive parameters including fertilization, embryo development, and the number of births. RNA transcriptome sequencing was performed to determine differential mRNA expression, and the interaction between Kdm2a and the PI3K/Akt pathway was studied with a specific inhibitor and activator. Our results revealed that Kdm2a was continuously expressed in preimplantation embryos and loss of maternal Kdm2a suppressed the morula-to-blastocyst transition, which may have been responsible for female subfertility. After the deletion of Kdm2a, the global H3K36me2 methylation in mutant embryos was markedly increased, but the expression of E-cadherin decreased significantly in morula embryos compared to controls. Mechanistically, RNA-seq analysis revealed that deficiency of maternal Kdm2a altered the mRNA expression profile, especially in the PI3K/Akt signaling pathway. Interestingly, the addition of a PI3K/Akt inhibitor (LY294002) to the culture medium blocked embryo development at the stage of morula; however, the developmental block caused by maternal Kdm2a loss was partially rescued with a PI3K/Akt activator (SC79). In summary, our results indicate that loss of Kdm2a influences the transcriptome profile and disrupts the PI3K/Akt signaling pathway during the development of preimplantation embryo. This can result in embryo block at the morula stage and female subfertility, which suggests that maternal Kdm2a is a potential partial redundancy with other genes encoding enzymes in the dynamics of early embryonic development. Our results provide further insight into the role of histone modification, especially on Kdm2a, in preimplantation embryonic development in mice.
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Affiliation(s)
- Xianrong Xiong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, 610041, China; Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu, 610041, China
| | - Manzhen Yang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, 610041, China
| | - Zhuo Hai
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu, 610041, China
| | - Xixi Fei
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, 610041, China
| | - Yanjin Zhu
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu, 610041, China
| | - Bangting Pan
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, 610041, China
| | - Qinhui Yang
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu, 610041, China
| | - Yumian Xie
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, 610041, China
| | - Yuying Cheng
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu, 610041, China
| | - Yan Xiong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, 610041, China
| | - Daoliang Lan
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, 610041, China
| | - Wei Fu
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu, 610041, China
| | - Jian Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, 610041, China; Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu, 610041, China.
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19
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Xiong X, Huang X, Zhu Y, Hai Z, Fei X, Pan B, Yang Q, Xiong Y, Fu W, Lan D, Zhang X, Li J. Testis-specific knockout of Kdm2a reveals nonessential roles in male fertility but partially compromises spermatogenesis. Theriogenology 2023; 209:9-20. [PMID: 37354760 DOI: 10.1016/j.theriogenology.2023.06.008] [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: 12/27/2022] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 06/26/2023]
Abstract
Lysine-specific histone demethylase 2 (Kdm2a) is a regulatory factor of histone modifications that participates in gametogenesis and embryonic development. The mis-regulation of Kdm2a can lead to aberrant gene expression, thereby contributing to abnormal cell proliferation, differentiation, apoptosis, and tumorigenesis. However, due to the potential confounding effects that are secondary to the loss of Kdm2a function from the soma in existing whole-animal mutants, the in vivo function of Kdm2a in spermatogenesis for male fertility remains unknown. Herein, we focus on exploring the spatiotemporal expression profile and biological functions of Kdm2a in the spermatogenesis and fertility of male mice. A testis-specific knockout Kdm2a model (Kdm2a cKO) was established by using the Stra8-Cre/loxP recombinase system to explore the roles of Kdm2a in male fertility. Our results showed that Kdm2a was ubiquitously expressed and dynamically distributed in multiple tissues and cell types in the testis of mice. Surprisingly, Kdm2a-deficient adult males were completely fertile and comparable with their control (Kdm2aflox/flox) counterparts. Despite the significantly reduced total number of sperm and density of seminiferous tubules in Kdm2a cKO testis accompanied by the degeneration of spermatogenesis, the fertilization ability and embryonic developmental competence of the Kdm2a cKO were comparable with those of their control littermates, suggesting that Kdm2a disruption did not markedly affect male fertility, at least during younger ages. Furthermore, Kdm2a homozygous mutants exhibited a lower total number and motility of sperm than the control group and showed notably affected serum 17β-estradiol concentration. Interestingly, the transcriptome sequencing revealed that the loss of Kdm2a remarkably upregulated the expression level of Kdm2b. This effect, in turn, may induce compensative effects in the case of Kdm2a deficiency to maintain normal male reproduction. Together, our results reveal that Kdm2a shows spatiotemporal expression during testicular development and that its loss is insufficient to compromise the production of spermatozoa completely. The homologous Kdm2b gene might compensate for the loss of Kdm2a. Our work provides a novel Kdm2a cKO mouse allowing for the efficient deletion of Kdm2a in a testis-specific manner, and further investigated the biological function of Kdm2a and the compensatory effects of Kdm2b. Our study will advance our understanding of underlying mechanisms in spermatogenesis and male fertility.
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Affiliation(s)
- Xianrong Xiong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, PR China
| | - Xiangyue Huang
- Key Laboratory for Animal Science of State Ethnic Affairs Commission, Southwest Minzu University, Chengdu, Sichuan, 610041, PR China
| | - Yanjin Zhu
- Key Laboratory for Animal Science of State Ethnic Affairs Commission, Southwest Minzu University, Chengdu, Sichuan, 610041, PR China
| | - Zhuo Hai
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, PR China
| | - Xixi Fei
- Key Laboratory for Animal Science of State Ethnic Affairs Commission, Southwest Minzu University, Chengdu, Sichuan, 610041, PR China
| | - Bangting Pan
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, PR China
| | - Qinhui Yang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, PR China
| | - Yan Xiong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, PR China
| | - Wei Fu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, PR China
| | - Daoliang Lan
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, PR China
| | - Xiaojian Zhang
- Center for Assisted Reproduction, Sichuan Academy of Medical Science, Sichuan Provincial People's Hospital, Chengdu, 610072, PR China
| | - Jian Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, PR China; Key Laboratory for Animal Science of State Ethnic Affairs Commission, Southwest Minzu University, Chengdu, Sichuan, 610041, PR China.
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20
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Han D, Schaffner SH, Davies JP, Benton ML, Plate L, Nordman JT. BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels. Proc Natl Acad Sci U S A 2023; 120:e2305092120. [PMID: 37722046 PMCID: PMC10523488 DOI: 10.1073/pnas.2305092120] [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: 03/29/2023] [Accepted: 08/11/2023] [Indexed: 09/20/2023] Open
Abstract
Histone modifications are critical for regulating chromatin structure and gene expression. Dysregulation of histone modifications likely contributes to disease states and cancer. Depletion of the chromatin-binding protein BRWD3 (Bromodomain and WD repeat-containing protein 3), a known substrate-specificity factor of the Cul4-DDB1 E3 ubiquitin ligase complex, results in increased H3K4me1 (H3 lysine 4 monomethylation) levels. The underlying mechanism linking BRWD3 and H3K4 methylation, however, has yet to be defined. Here, we show that depleting BRWD3 not only causes an increase in H3K4me1 levels but also causes a decrease in H3K4me3 (H3 lysine 4 trimethylation) levels, indicating that BRWD3 influences H3K4 methylation more broadly. Using immunoprecipitation coupled to quantitative mass spectrometry, we identified an interaction between BRWD3 and the H3K4-specific lysine demethylase 5 (KDM5/Lid), an enzyme that removes tri- and dimethyl marks from H3K4. Moreover, analysis of ChIP-seq (chromatin immunoprecipitation sequencing) data revealed that BRWD3 and KDM5 are significantly colocalized throughout the genome and H3K4me3 are highly enriched at BRWD3 binding sites. We show that BRWD3 promotes K48-linked polyubiquitination and degradation of KDM5 and that KDM5 degradation is dependent on both BRWD3 and Cul4. Critically, depleting KDM5 fully restores altered H3K4me3 levels and partially restores H3K4me1 levels upon BRWD3 depletion. Together, our results demonstrate that BRWD3 regulates KDM5 activity to balance H3K4 methylation levels.
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Affiliation(s)
- Dongsheng Han
- Department of Biological Sciences, Vanderbilt University, Nashville, TN37212
| | | | - Jonathan P. Davies
- Department of Biological Sciences, Vanderbilt University, Nashville, TN37212
| | | | - Lars Plate
- Department of Biological Sciences, Vanderbilt University, Nashville, TN37212
- Department of Chemistry, Vanderbilt University, Nashville, TN37212
| | - Jared T. Nordman
- Department of Biological Sciences, Vanderbilt University, Nashville, TN37212
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21
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Liao J, Song S, Gusscott S, Fu Z, VanderKolk I, Busscher BM, Lau KH, Brind’Amour J, Szabó PE. Establishment of paternal methylation imprint at the H19/Igf2 imprinting control region. SCIENCE ADVANCES 2023; 9:eadi2050. [PMID: 37672574 PMCID: PMC10482337 DOI: 10.1126/sciadv.adi2050] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 08/02/2023] [Indexed: 09/08/2023]
Abstract
The insulator model explains the workings of the H19 and Igf2 imprinted domain in the soma, where insulation of the Igf2 promoter from its enhancers occurs by CTCF in the maternally inherited unmethylated chromosome but not the paternally inherited methylated allele. The molecular mechanism that targets paternal methylation imprint establishment to the imprinting control region (ICR) in the male germline is unknown. We tested the function of prospermatogonia-specific broad low-level transcription in this process using mouse genetics. Paternal imprint establishment was abnormal when transcription was stopped at the entry point to the ICR. The germline epimutation persisted into the paternal allele of the soma, resulting in reduced Igf2 in fetal organs and reduced fetal growth, consistent with the insulator model and insulin-like growth factor 2 (IGF2)'s role as fetal growth factor. These results collectively support the role of broad low-level transcription through the H19/Igf2 ICR in the establishment of its paternal methylation imprint in the male germ line, with implications for Silver-Russell syndrome.
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Affiliation(s)
- Ji Liao
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Sangmin Song
- Division of Molecular and Cellular Biology, City of Hope Cancer Center, Duarte, CA 91010, USA
| | - Samuel Gusscott
- Département de Biomédecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Quebec J2S, Canada
| | - Zhen Fu
- Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Ivan VanderKolk
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | | | - Kin H. Lau
- Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Julie Brind’Amour
- Département de Biomédecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Quebec J2S, Canada
| | - Piroska E. Szabó
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
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22
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Anvar Z, Chakchouk I, Sharif M, Mahadevan S, Nasiotis ET, Su L, Liu Z, Wan YW, Van den Veyver IB. Loss of the Maternal Effect Gene Nlrp2 Alters the Transcriptome of Ovulated Mouse Oocytes and Impacts Expression of Histone Demethylase KDM1B. Reprod Sci 2023; 30:2780-2793. [PMID: 36976514 PMCID: PMC10524210 DOI: 10.1007/s43032-023-01218-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 03/09/2023] [Indexed: 03/29/2023]
Abstract
The subcortical maternal complex (SCMC) is a multiprotein complex in oocytes and preimplantation embryos that is encoded by maternal effect genes. The SCMC is essential for zygote-to-embryo transition, early embryogenesis, and critical zygotic cellular processes, including spindle positioning and symmetric division. Maternal deletion of Nlrp2, which encodes an SCMC protein, results in increased early embryonic loss and abnormal DNA methylation in embryos. We performed RNA sequencing on pools of meiosis II (MII) oocytes from wild-type and Nlrp2-null female mice that were isolated from cumulus-oocyte complexes (COCs) after ovarian stimulation. Using a mouse reference genome-based analysis, we found 231 differentially expressed genes (DEGs) in Nlrp2-null compared to WT oocytes (123 up- and 108 downregulated; adjusted p < 0.05). The upregulated genes include Kdm1b, a H3K4 histone demethylase required during oocyte development for the establishment of DNA methylation marks at CpG islands, including those at imprinted genes. The identified DEGs are enriched for processes involved in neurogenesis, gland morphogenesis, and protein metabolism and for post-translationally methylated proteins. When we compared our RNA sequencing data to an oocyte-specific reference transcriptome that contains many previously unannotated transcripts, we found 228 DEGs, including genes not identified with the first analysis. Interestingly, 68% and 56% of DEGs from the first and second analyses, respectively, overlap with oocyte-specific hyper- and hypomethylated domains. This study shows that there are substantial changes in the transcriptome of mouse MII oocytes from female mice with loss of function of Nlrp2, a maternal effect gene that encodes a member of the SCMC.
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Affiliation(s)
- Zahra Anvar
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA
- Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Imen Chakchouk
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA
- Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Momal Sharif
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA
- Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Sangeetha Mahadevan
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA
- Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Eleni Theodora Nasiotis
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA
- Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Li Su
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA
- Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Zhandong Liu
- Department of Pediatrics - Neurology, Baylor College of Medicine, Houston, TX, USA
| | - Ying-Wooi Wan
- Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
| | - Ignatia B Van den Veyver
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA.
- Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
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23
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Uehara R, Au Yeung WK, Toriyama K, Ohishi H, Kubo N, Toh H, Suetake I, Shirane K, Sasaki H. The DNMT3A ADD domain is required for efficient de novo DNA methylation and maternal imprinting in mouse oocytes. PLoS Genet 2023; 19:e1010855. [PMID: 37527244 PMCID: PMC10393158 DOI: 10.1371/journal.pgen.1010855] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 07/03/2023] [Indexed: 08/03/2023] Open
Abstract
Establishment of a proper DNA methylation landscape in mammalian oocytes is important for maternal imprinting and embryonic development. De novo DNA methylation in oocytes is mediated by the DNA methyltransferase DNMT3A, which has an ATRX-DNMT3-DNMT3L (ADD) domain that interacts with histone H3 tail unmethylated at lysine-4 (H3K4me0). The domain normally blocks the methyltransferase domain via intramolecular interaction and binding to histone H3K4me0 releases the autoinhibition. However, H3K4me0 is widespread in chromatin and the role of the ADD-histone interaction has not been studied in vivo. We herein show that amino-acid substitutions in the ADD domain of mouse DNMT3A cause dwarfism. Oocytes derived from homozygous females show mosaic loss of CG methylation and almost complete loss of non-CG methylation. Embryos derived from such oocytes die in mid-to-late gestation, with stochastic and often all-or-none-type CG-methylation loss at imprinting control regions and misexpression of the linked genes. The stochastic loss is a two-step process, with loss occurring in cleavage-stage embryos and regaining occurring after implantation. These results highlight an important role for the ADD domain in efficient, and likely processive, de novo CG methylation and pose a model for stochastic inheritance of epigenetic perturbations in germ cells to the next generation.
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Affiliation(s)
- Ryuji Uehara
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Wan Kin Au Yeung
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Keisuke Toriyama
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Hiroaki Ohishi
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Division of Gene Expression Dynamics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Naoki Kubo
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Hidehiro Toh
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Advanced Genomics Center, National Institute of Genetics, Mishima, Japan
| | - Isao Suetake
- Department of Nutrition Science, Nakamura Gakuen University, Fukuoka, Japan
| | - Kenjiro Shirane
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Department of Genome Biology, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Hiroyuki Sasaki
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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24
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Wu YY, Xu YM, Lau ATY. Epigenetic effects of herbal medicine. Clin Epigenetics 2023; 15:85. [PMID: 37179342 PMCID: PMC10183144 DOI: 10.1186/s13148-023-01481-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 04/08/2023] [Indexed: 05/15/2023] Open
Abstract
Epigenetic memory is essential for life that governs the predefined functional features of cells. Recent evidence has indicated that the epigenetic modification provides a potential link to gene expression changes that may be involved in the development of various chronic diseases, and targeting the epigenome becomes a plausible method for treating diseases. Traditional herbal medicine has gradually entered the vision of researchers due to its low toxicity and its effectiveness in treating diseases. As a matter of fact, researchers found that the possessed epigenetic modification capacity of herbal medicine had the ability to combat the progression of the disease, such as various types of cancer, diabetes, inflammation, amnesia, liver fibrosis, asthma, and hypertension-induced renal injury. Studies on the epigenetic effects of herbal medicine will provide valuable insights into the molecular mechanisms of human diseases, which may lead to new therapeutic approaches and diagnoses. Thus, this review summarized the impact of herbal medicine and its bioactive components on disease epigenome as examples of how utilization of epigenetic plasticity could be useful as the basis for the future development of targeted therapies in chronic diseases.
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Affiliation(s)
- Yu-Yao Wu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, 515041, Guangdong, People's Republic of China
| | - Yan-Ming Xu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, 515041, Guangdong, People's Republic of China
| | - Andy T Y Lau
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, 515041, Guangdong, People's Republic of China.
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25
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Caroli J, Mattevi A. The NPAC-LSD2 complex in nucleosome demethylation. Enzymes 2023; 53:97-111. [PMID: 37748839 DOI: 10.1016/bs.enz.2023.03.003] [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] [Indexed: 09/27/2023]
Abstract
NPAC is a transcriptional co-activator widely associated with the H3K36me3 epigenetic marks present in the gene bodies. NPAC plays a fundamental role in RNA polymerase progression, and its depletion downregulates gene transcription. In this chapter, we review the current knowledge on the functional and structural features of this multi-domain protein. NPAC (also named GLYR1 or NP60) contains a PWWP motif, a chromatin binder and epigenetic reader that is proposed to weaken the DNA-histone contacts facilitating polymerase passage through the nucleosomes. The C-terminus of NPAC is a catalytically inactive dehydrogenase domain that forms a stable and rigid tetramer acting as an oligomerization module for the formation of co-transcriptional multimeric complexes. The PWWP and dehydrogenase domains are connected by a long, mostly disordered, linker that comprises putative sites for protein and DNA interactions. A short dodecapeptide sequence (residues 214-225) forms the binding site for LSD2, a flavin-dependent lysine-specific histone demethylase. This stretch of residues binds on the surface of LSD2 and facilitates the capture and processing of the H3 tail in the nucleosome context, thus promoting the H3K4me1/2 epigenetic mark removal. LSD2 is associated with other two chromatin modifiers, G9a and NSD3. The LSD2-G9a-NSD3 complex modifies the pattern of the post translational modifications deposited on histones, thus converting the relaxed chromatin into a transcriptionally refractory state after the RNA polymerase passage. NPAC is a scaffolding factor that organizes and coordinates the epigenetic activities required for optimal transcription elongation.
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Affiliation(s)
- Jonatan Caroli
- Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, Italy
| | - Andrea Mattevi
- Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, Italy.
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26
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Su Z, Kon N, Yi J, Zhao H, Zhang W, Tang Q, Li H, Kobayashi H, Li Z, Duan S, Liu Y, Olive KP, Zhang Z, Honig B, Manfredi JJ, Rustgi AK, Gu W. Specific regulation of BACH1 by the hotspot mutant p53 R175H reveals a distinct gain-of-function mechanism. NATURE CANCER 2023; 4:564-581. [PMID: 36973430 PMCID: PMC10320414 DOI: 10.1038/s43018-023-00532-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 02/21/2023] [Indexed: 03/29/2023]
Abstract
Although the gain of function (GOF) of p53 mutants is well recognized, it remains unclear whether different p53 mutants share the same cofactors to induce GOFs. In a proteomic screen, we identified BACH1 as a cellular factor that recognizes the p53 DNA-binding domain depending on its mutation status. BACH1 strongly interacts with p53R175H but fails to effectively bind wild-type p53 or other hotspot mutants in vivo for functional regulation. Notably, p53R175H acts as a repressor for ferroptosis by abrogating BACH1-mediated downregulation of SLC7A11 to enhance tumor growth; conversely, p53R175H promotes BACH1-dependent tumor metastasis by upregulating expression of pro-metastatic targets. Mechanistically, p53R175H-mediated bidirectional regulation of BACH1 function is dependent on its ability to recruit the histone demethylase LSD2 to target promoters and differentially modulate transcription. These data demonstrate that BACH1 acts as a unique partner for p53R175H in executing its specific GOFs and suggest that different p53 mutants induce their GOFs through distinct mechanisms.
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Affiliation(s)
- Zhenyi Su
- Institute for Cancer Genetics, and Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Ning Kon
- Institute for Cancer Genetics, and Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Jingjie Yi
- Institute for Cancer Genetics, and Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Haiqing Zhao
- Departments of Biochemistry and Molecular Biophysics, Systems Biology, and Medical Sciences in Medicine, Zuckerman Institute Columbia University, New York, NY, USA
| | - Wanwei Zhang
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Qiaosi Tang
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Huan Li
- Institute for Cancer Genetics, and Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Hiroki Kobayashi
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Zhiming Li
- Institute for Cancer Genetics, and Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Shoufu Duan
- Institute for Cancer Genetics, and Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Yanqing Liu
- Institute for Cancer Genetics, and Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Kenneth P Olive
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Zhiguo Zhang
- Institute for Cancer Genetics, and Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Barry Honig
- Departments of Biochemistry and Molecular Biophysics, Systems Biology, and Medical Sciences in Medicine, Zuckerman Institute Columbia University, New York, NY, USA
| | - James J Manfredi
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Anil K Rustgi
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Wei Gu
- Institute for Cancer Genetics, and Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
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27
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Han D, Schaffner SH, Davies JP, Lauren Benton M, Plate L, Nordman JT. BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.28.534572. [PMID: 37034668 PMCID: PMC10081218 DOI: 10.1101/2023.03.28.534572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/22/2023]
Abstract
Histone modifications are critical for regulating chromatin structure and gene expression. Dysregulation of histone modifications likely contributes to disease states and cancer. Depletion of the chromatin-binding protein BRWD3, a known substrate-specificity factor of the Cul4-DDB1 E3 ubiquitin ligase complex, results in increased in H3K4me1 levels. The underlying mechanism linking BRWD3 and H3K4 methylation, however, has yet to be defined. Here, we show that depleting BRWD3 not only causes an increase in H3K4me1 levels, but also causes a decrease in H3K4me3 levels, indicating that BRWD3 influences H3K4 methylation more broadly. Using immunoprecipitation coupled to quantitative mass spectrometry, we identified an interaction between BRWD3 and the H3K4-specific demethylase 5 (KDM5/Lid), an enzyme that removes tri- and di- methyl marks from H3K4. Moreover, analysis of ChIP-seq data revealed that BRWD3 and KDM5 are significantly co- localized throughout the genome and that sites of H3K4me3 are highly enriched at BRWD3 binding sites. We show that BRWD3 promotes K48-linked polyubiquitination and degradation of KDM5 and that KDM5 degradation is dependent on both BRWD3 and Cul4. Critically, depleting KDM5 fully restores altered H3K4me3 levels and partially restores H3K4me1 levels upon BRWD3 depletion. Together, our results demonstrate that BRWD3 regulates KDM5 activity to balance H3K4 methylation levels.
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Affiliation(s)
- Dongsheng Han
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37212, USA
| | | | - Jonathan P. Davies
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37212, USA
| | | | - Lars Plate
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37212, USA
- Department of Chemistry, Vanderbilt University, Nashville, TN, 37212, USA
| | - Jared T. Nordman
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37212, USA
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Li Z, Yuan Y, Wang P, Zhang Z, Ma H, Sun Y, Zhang X, Li X, Qiao Y, Zhang F, Su Y, Song J, Xie Z, Li L, Ma L, Ma J, Zhang Z. Design, synthesis and in vitro/in vivo anticancer activity of tranylcypromine-based triazolopyrimidine analogs as novel LSD1 inhibitors. Eur J Med Chem 2023; 253:115321. [PMID: 37037137 DOI: 10.1016/j.ejmech.2023.115321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/26/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023]
Abstract
Histone lysine specific demethylase 1 (LSD1) is responsible for the demethylation of mono-/dimethylated lysine residue on histone proteins. LSD1 plays an extensive and essential role in the pathogenesis and progression of many human diseases such as cancers, and thus is becoming an attractive therapeutic target for cancer treatment. Tranylcypromine (TCP) is an important chemical template for developing irreversible LSD1 inhibitors, representing a major chemotype of clinical candidates. Here we report a novel pool of TCP derivatives with triazolopyrimidine as a privileged heterocylic motif. Starting from ticagrelor, a clinically available antiplatelet agent, as a hit compound, our medicinal efforts have led to the identification of compound 9j with nanomolar inhibitory potency against LSD1 as well as broad-spectrum antiproliferative activities against tumor cells. Enzyme studies show that compound 9j is selective over MAO-A/B enzymes, and also cellular active to elevate the expression of H3K4me2 by inhibiting LSD1 in cells. Furthermore, in a H1650 xenograft mouse model, oral administration of compound 9j at low 10 and 20 mg/kg dosages could enable a significant reduction in tumor size and a remarkable extension of survival. The current work is expected to provide an additional strategy to achieve new TCP-based LSD1 inhibitors.
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29
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Sutopo NC, Kim JH, Cho JY. Role of histone methylation in skin cancers: Histone methylation-modifying enzymes as a new class of targets for skin cancer treatment. Biochim Biophys Acta Rev Cancer 2023; 1878:188865. [PMID: 36841366 DOI: 10.1016/j.bbcan.2023.188865] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/17/2023] [Accepted: 02/17/2023] [Indexed: 02/27/2023]
Abstract
Histone methylation, one of the most prominent epigenetic modifications, plays a vital role in gene transcription, and aberrant histone methylation levels cause tumorigenesis. Histone methylation is a reversible enzyme-dependent reaction, and histone methyltransferases and demethylases are involved in this reaction. This review addresses the biological and clinical relevance of these histone methylation-modifying enzymes for skin cancer. In particular, the roles of histone lysine methyltransferases, histone arginine methyltransferase, lysine-specific demethylases, and JmjC demethylases in skin cancer are discussed in detail. In addition, we summarize the efficacy of several epigenetic inhibitors targeting histone methylation-modifying enzymes in cutaneous cancers, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. In conclusion, we propose histone methylation-modifying enzymes as novel targets for next-generation pharmaceuticals in the treatment of skin cancers and further provide a rationale for the development of epigenetic drugs (epidrugs) that target specific histone methylases/demethylases in cutaneous tumors.
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Affiliation(s)
| | - Ji Hye Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea; Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea.
| | - Jae Youl Cho
- Department of Biocosmetics, Sungkyunkwan University, Suwon 16419, Republic of Korea; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea; Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea.
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Noce B, Di Bello E, Fioravanti R, Mai A. LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials. Front Pharmacol 2023; 14:1120911. [PMID: 36817147 PMCID: PMC9932783 DOI: 10.3389/fphar.2023.1120911] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 01/20/2023] [Indexed: 02/05/2023] Open
Abstract
Histone lysine-specific demethylase 1 (LSD1/KDM1A) was first identified in 2004 as an epigenetic enzyme able to demethylate specific lysine residues of histone H3, namely H3K4me1/2 and H3K9me1/2, using FAD as the cofactor. It is ubiquitously overexpressed in many types of cancers (breast, gastric, prostate, hepatocellular, and esophageal cancer, acute myeloid leukemia, and others) leading to block of differentiation and increase of proliferation, migration and invasiveness at cellular level. LSD1 inhibitors can be grouped in covalent and non-covalent agents. Each group includes some hybrid compounds, able to inhibit LSD1 in addition to other target(s) at the same time (dual or multitargeting compounds). To date, 9 LSD1 inhibitors have entered clinical trials, for hematological and/or solid cancers. Seven of them (tranylcypromine, iadademstat (ORY-1001), bomedemstat (IMG-7289), GSK-2879552, INCB059872, JBI-802, and Phenelzine) covalently bind the FAD cofactor, and two are non-covalent LSD1 inhibitors [pulrodemstat (CC-90011) and seclidemstat (SP-2577)]. Another TCP-based LSD1/MAO-B dual inhibitor, vafidemstat (ORY-2001), is in clinical trial for Alzheimer's diseases and personality disorders. The present review summarizes the structure and functions of LSD1, its pathological implications in cancer and non-cancer diseases, and the identification of LSD1 covalent and non-covalent inhibitors with different chemical scaffolds, including those involved in clinical trials, highlighting their potential as potent and selective anticancer agents.
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Affiliation(s)
- Beatrice Noce
- Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Rome, Italy
| | - Elisabetta Di Bello
- Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Rome, Italy
| | - Rossella Fioravanti
- Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Rome, Italy,*Correspondence: Rossella Fioravanti,
| | - Antonello Mai
- Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Rome, Italy,Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Rome, Italy
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31
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Song Y, Wang S, Yu B. Structural and Functional Landscape of FAD-Dependent Histone Lysine Demethylases for New Drug Discovery. J Med Chem 2023; 66:71-94. [PMID: 36537915 DOI: 10.1021/acs.jmedchem.2c01324] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Small molecules targeting the flavin adenine dinucleotide (FAD)-dependent histone lysine demethylase LSD family have displayed therapeutic promise against various diseases. Nine clinical candidates targeting the classic demethylase-dependent functions of the LSD family are currently being investigated for treating cancers, neurodegenerative diseases, etc. Moreover, targeting noncatalytic functions of LSDs also represents an emerging strategy for treating human diseases. In this Perspective, we provide full structural and functional landscape of the LSD family and action modes of different types of LSD inhibitors including natural products, peptides, and synthetic compounds, aiming to reveal new druggable space for the design of new LSD inhibitors. Particularly, we first classify these inhibitors into three types based on their unique binding modes. Additionally, the strategies targeting the demethylase-independent functions of LSDs are also briefly discussed. This Perspective may benefit the discovery of new LSD inhibitors for probing LSD biology and/or treating human diseases.
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Affiliation(s)
- Yihui Song
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Shu Wang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Bin Yu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
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32
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Cao J, Yan Q. Lysine Demethylation in Pathogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1433:1-14. [PMID: 37751133 DOI: 10.1007/978-3-031-38176-8_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Abstract
Epigenetics has major impact on normal development and pathogenesis. Regulation of histone methylation on lysine and arginine residues is a major epigenetic mechanism and affects various processes including transcription and DNA repair. Histone lysine methylation is reversible and is added by histone lysine methyltransferases and removed by histone lysine demethylases. As these enzymes are also capable of writing or erasing lysine modifications on non-histone substrates, they were renamed to lysine demethylases (KDMs) in 2007. Since the discovery of the first lysine demethylase LSD1/KDM1A in 2004, eight more subfamilies of lysine demethylases have been identified and further characterized. The joint efforts by academia and industry have led to the development of potent and specific small molecule inhibitors of KDMs for treatment of cancer and several other diseases. Some of these inhibitors have already entered clinical trials since 2013, less than 10 years after the discovery of the first KDM. In this chapter, we briefly summarize the major roles of histone demethylases in normal development and human diseases and the efforts to target these enzymes to treat various diseases.
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Affiliation(s)
- Jian Cao
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA.
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08901, USA.
| | - Qin Yan
- Department of Pathology, Yale Cancer Center, Yale Stem Cell Center, Yale Center for Immuno-Oncology, Yale Center for Research on Aging, Yale School of Medicine, New Haven, CT, 06520, USA.
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Epimutations and Their Effect on Chromatin Organization: Exciting Avenues for Cancer Treatment. Cancers (Basel) 2022; 15:cancers15010215. [PMID: 36612210 PMCID: PMC9818548 DOI: 10.3390/cancers15010215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/14/2022] [Accepted: 12/28/2022] [Indexed: 12/31/2022] Open
Abstract
The three-dimensional architecture of genomes is complex. It is organized as fibers, loops, and domains that form high-order structures. By using different chromosome conformation techniques, the complex relationship between transcription and genome organization in the three-dimensional organization of genomes has been deciphered. Epigenetic changes, such as DNA methylation and histone modification, are the hallmark of cancers. Tumor initiation, progression, and metastasis are linked to these epigenetic modifications. Epigenetic inhibitors can reverse these altered modifications. A number of epigenetic inhibitors have been approved by FDA that target DNA methylation and histone modification. This review discusses the techniques involved in studying the three-dimensional organization of genomes, DNA methylation and histone modification, epigenetic deregulation in cancer, and epigenetic therapies targeting the tumor.
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Hou C, Ye Z, Yang S, Jiang Z, Wang J, Wang E. Lysine demethylase 1B (Kdm1b) enhances somatic reprogramming through inducing pluripotent gene expression and promoting cell proliferation. Exp Cell Res 2022; 420:113339. [PMID: 36075448 DOI: 10.1016/j.yexcr.2022.113339] [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: 02/22/2022] [Revised: 08/28/2022] [Accepted: 08/31/2022] [Indexed: 11/28/2022]
Abstract
Lysine demethylase 1B (Kdm1b) is known as an epigenetic modifier with demethylase activity against H3K4 and H3K9 histones and plays an important role in tumor progression and tumor stem cell enrichment. In this study, we attempted to elucidate the role of Kdm1b in somatic cell reprogramming. We found that exogenous expression of Kdm1b in human dermal fibroblasts (HDFs) can influence the epigenetic modifications of histones. Subsequent analysis further suggests that the overexpression of Kdm1b can promote cell proliferation, reprogram metabolism and inhibit cell apoptosis. In addition, a series of multipotent factors including Sox2 and Nanog, and several epigenetic factors that may reduce epigenetic barriers were upregulated to varying degrees. More importantly, HDFs transfected with the combination of Oct4 (POU5F1), Sox2, Klf4 and c-Myc and Kdm1b (OSKMK) achieved higher reprogramming efficiency. Therefore, we suggest that Kdm1b is an important epigenetic factor associated with pluripotency.
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Affiliation(s)
- Cuicui Hou
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, PR China; College of Chemistry, Jilin University, Changchun, Jilin, 130021, PR China
| | - Zhikai Ye
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, PR China
| | - Songqin Yang
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, PR China
| | - Zhenlong Jiang
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, PR China.
| | - Jin Wang
- Department of Chemistry, Physics and Applied Mathematics, State University of New York at Stony Brook, Stony Brook, NY, 11794-3400, United States.
| | - Erkang Wang
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, PR China; College of Chemistry, Jilin University, Changchun, Jilin, 130021, PR China.
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35
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Li Y, Zhao Y, Li X, Zhai L, Zheng H, Yan Y, Fu Q, Ma J, Fu H, Zhang Z, Li Z. Biological and therapeutic role of LSD1 in Alzheimer’s diseases. Front Pharmacol 2022; 13:1020556. [PMID: 36386192 PMCID: PMC9640401 DOI: 10.3389/fphar.2022.1020556] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/13/2022] [Indexed: 12/02/2022] Open
Abstract
Alzheimer’s disease (AD) is a common chronic neurodegenerative disease characterized by cognitive learning and memory impairments, however, current treatments only provide symptomatic relief. Lysine-specific demethylase 1 (LSD1), regulating the homeostasis of histone methylation, plays an important role in the pathogenesis of many neurodegenerative disorders. LSD1 functions in regulating gene expression via transcriptional repression or activation, and is involved in initiation and progression of AD. Pharmacological inhibition of LSD1 has shown promising therapeutic benefits for AD treatment. In this review, we attempt to elaborate on the role of LSD1 in some aspects of AD including neuroinflammation, autophagy, neurotransmitters, ferroptosis, tau protein, as well as LSD1 inhibitors under clinical assessments for AD treatment.
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Affiliation(s)
- Yu Li
- Department of Pharmacy, Yellow River Central Hospital of Yellow River Conservancy Commission, Zhengzhou, China
| | - Yuanyuan Zhao
- Department of Pharmacy, Yellow River Central Hospital of Yellow River Conservancy Commission, Zhengzhou, China
| | - Xiaona Li
- Department of Pharmacy, Yellow River Central Hospital of Yellow River Conservancy Commission, Zhengzhou, China
| | - Liuqun Zhai
- Department of Pharmacy, Yellow River Central Hospital of Yellow River Conservancy Commission, Zhengzhou, China
| | - Hua Zheng
- Department of Pharmacy, Yellow River Central Hospital of Yellow River Conservancy Commission, Zhengzhou, China
| | - Ying Yan
- Department of Pharmacy, Yellow River Central Hospital of Yellow River Conservancy Commission, Zhengzhou, China
| | - Qiang Fu
- Department of Pharmacy, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jinlian Ma
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China
| | - Haier Fu
- Department of Pharmacy, Yellow River Central Hospital of Yellow River Conservancy Commission, Zhengzhou, China
- *Correspondence: Haier Fu, ; Zhenqiang Zhang, ; Zhonghua Li,
| | - Zhenqiang Zhang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China
- *Correspondence: Haier Fu, ; Zhenqiang Zhang, ; Zhonghua Li,
| | - Zhonghua Li
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China
- *Correspondence: Haier Fu, ; Zhenqiang Zhang, ; Zhonghua Li,
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36
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Xiong X, Zhang X, Yang M, Zhu Y, Yu H, Fei X, Mastuda F, Lan D, Xiong Y, Fu W, Yin S, Li J. Oocyte-Specific Knockout of Histone Lysine Demethylase KDM2a Compromises Fertility by Blocking the Development of Follicles and Oocytes. Int J Mol Sci 2022; 23:ijms231912008. [PMID: 36233308 PMCID: PMC9570323 DOI: 10.3390/ijms231912008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/05/2022] Open
Abstract
The methylation status of histones plays a crucial role in many cellular processes, including follicular and oocyte development. Lysine-specific demethylase 2a (KDM2a) has been reported to be closely associated with gametogenesis and reproductive performance, but the specific function and regulatory mechanism have been poorly characterized in vivo. We found KDM2a to be highly expressed in growing follicles and oocytes of mice in this study. To elucidate the physiological role of Kdm2a, the zona pellucida 3-Cre (Zp3-Cre)/LoxP system was used to generate an oocyte Kdm2a conditional knockout (Zp3-Cre; Kdm2aflox/flox, termed Kdm2a cKO) model. Our results showed that the number of pups was reduced by approximately 50% in adult Kdm2a cKO female mice mating with wildtype males than that of the control (Kdm2aflox/flox) group. To analyze the potential causes, the ovaries of Kdm2a cKO mice were subjected to histological examination, and results indicated an obvious difference in follicular development between Kdm2a cKO and control female mice and partial arrest at the primary antral follicle stage. The GVBD and matured rates of oocytes were also compromised after conditional knockout Kdm2a, and the morphological abnormal oocytes increased. Furthermore, the level of 17β-estradiol of Kdm2a cKO mice was only 60% of that in the counterparts, and hormone sensitivity decreased as the total number of ovulated and matured oocytes decreased after superovulation. After deletion of Kdm2a, the patterns of H3K36me2/3 in GVBD-stage oocytes were remarkedly changed. Transcriptome sequencing showed that the mRNA expression profiles in Kdm2a cKO oocytes were significantly different, and numerous differentially expressed genes were involved in pathways regulating follicular and oocyte development. Taken together, these results indicated that the oocyte-specific knockout Kdm2a gene led to female subfertility, suggesting the crucial role of Kdm2a in epigenetic modification and follicular and oocyte development.
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Affiliation(s)
- Xianrong Xiong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
| | - Xiaojian Zhang
- Center for Assisted Reproduction, Sichuan Academy of Medical Science, Sichuan Provincial People’s Hospital, Chengdu 610072, China
| | - Manzhen Yang
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
| | - Yanjin Zhu
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
| | - Hailing Yu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Xixi Fei
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Fuko Mastuda
- Laboratory of Theriogenology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan
| | - Daoliang Lan
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Yan Xiong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Wei Fu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Shi Yin
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Jian Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
- Correspondence:
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37
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Yano S, Ishiuchi T, Abe S, Namekawa SH, Huang G, Ogawa Y, Sasaki H. Histone H3K36me2 and H3K36me3 form a chromatin platform essential for DNMT3A-dependent DNA methylation in mouse oocytes. Nat Commun 2022; 13:4440. [PMID: 35922445 PMCID: PMC9349174 DOI: 10.1038/s41467-022-32141-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 07/19/2022] [Indexed: 11/09/2022] Open
Abstract
Establishment of the DNA methylation landscape of mammalian oocytes, mediated by the DNMT3A-DNMT3L complex, is crucial for reproduction and development. In mouse oocytes, high levels of DNA methylation occur exclusively in the transcriptionally active regions, with moderate to low levels of methylation in other regions. Histone H3K36me3 mediates the high levels of methylation in the transcribed regions; however, it is unknown which histone mark guides the methylation in the other regions. Here, we show that, in mouse oocytes, H3K36me2 is highly enriched in the X chromosome and is broadly distributed across all autosomes. Upon H3K36me2 depletion, DNA methylation in moderately methylated regions is selectively affected, and a methylation pattern unique to the X chromosome is switched to an autosome-like pattern. Furthermore, we find that simultaneous depletion of H3K36me2 and H3K36me3 results in global hypomethylation, comparable to that of DNMT3A depletion. Therefore, the two histone marks jointly provide the chromatin platform essential for guiding DNMT3A-dependent DNA methylation in mouse oocytes.
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Affiliation(s)
- Seiichi Yano
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.,Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takashi Ishiuchi
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. .,Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi, Japan.
| | - Shusaku Abe
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Satoshi H Namekawa
- Department of Microbiology & Molecular Genetics, University of California Davis, Davis, CA, USA
| | - Gang Huang
- Department of Cell Systems & Anatomy and Department of Pathology & Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, San Antonio, TX, USA
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroyuki Sasaki
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
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38
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Maternal genetic factors in the development of congenital heart defects. Curr Opin Genet Dev 2022; 76:101961. [PMID: 35882070 DOI: 10.1016/j.gde.2022.101961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 06/20/2022] [Accepted: 06/25/2022] [Indexed: 11/24/2022]
Abstract
Congenital heart defects (CHDs) are among the most common, serious birth defects. However, the cause of CHDs is unknown for approximately half of affected individuals and there are few prevention strategies. Although not extensively investigated, maternal genes may contribute to CHD etiology by modifying the effects of maternal exposures (e.g. medications, nutrients), contributing to maternal phenotypes that are associated with an increased risk of CHDs in offspring (e.g. diabetes), or acting as maternal effect genes. Since maternal genes could serve as a target for the primary prevention of CHDs, efforts to further define the contribution of the maternal genome to CHD etiology are warranted.
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39
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Shirane K. The dynamic chromatin landscape and mechanisms of DNA methylation during mouse germ cell development. Gene 2022; 97:3-14. [PMID: 35431282 DOI: 10.1266/ggs.21-00069] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Epigenetic marks including DNA methylation (DNAme) play a critical role in the transcriptional regulation of genes and retrotransposons. Defects in DNAme are detected in infertility, imprinting disorders and congenital diseases in humans, highlighting the broad importance of this epigenetic mark in both development and disease. While DNAme in terminally differentiated cells is stably propagated following cell division by the maintenance DNAme machinery, widespread erasure and subsequent de novo establishment of this epigenetic mark occur early in embryonic development as well as in germ cell development. Combined with deep sequencing, low-input methods that have been developed in the past several years have enabled high-resolution and genome-wide mapping of both DNAme and histone post-translational modifications (PTMs) in rare cell populations including developing germ cells. Epigenome studies using these novel methods reveal an unprecedented view of the dynamic chromatin landscape during germ cell development. Furthermore, integrative analysis of chromatin marks in normal germ cells and in those deficient in chromatin-modifying enzymes uncovers a critical interplay between histone PTMs and de novo DNAme in the germline. This review discusses work on mechanisms of the erasure and subsequent de novo DNAme in mouse germ cells as well as the outstanding questions relating to the regulation of the dynamic chromatin landscape in germ cells.
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Affiliation(s)
- Kenjiro Shirane
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University
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40
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Qian J, Guo F. De novo programming: establishment of epigenome in mammalian oocytes. Biol Reprod 2022; 107:40-53. [PMID: 35552602 DOI: 10.1093/biolre/ioac091] [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: 12/20/2021] [Revised: 04/21/2022] [Accepted: 05/02/2022] [Indexed: 11/14/2022] Open
Abstract
Innovations in ultrasensitive and single-cell measurements enable us to study layers of genome regulation in the view of cellular and regulatory heterogeneity. Genome-scale mapping allows to evaluate epigenetic features and dynamics in different genomic contexts, including genebodies, CGIs, ICRs, promoters, PMDs, and repetitive elements. The epigenome of early embryos, fetal germ cells, and sperm has been extensively studied for the past decade, while oocytes remain less clear. Emerging evidence now supports the notion that transcription and chromatin accessibility precede de novo DNA methylation in both human and mouse oocytes. Recent studies also start to chart correlations among different histone modifications and DNA methylation. We discussed the potential mechanistic hierarchy by which shapes oocyte DNA methylome, also provided insights into the convergent and divergent features between human and mice.
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Affiliation(s)
- Jingjing Qian
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Fan Guo
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.,University of Chinese Academy of Sciences, Beijing 100049, China
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Tang D, He J, Dai Y, Geng X, Leng Q, Jiang H, Sun R, Xu S. Targeting KDM1B-dependent miR-215-AR-AGR2-axis promotes sensitivity to enzalutamide-resistant prostate cancer. Cancer Gene Ther 2022; 29:543-557. [PMID: 33854217 DOI: 10.1038/s41417-021-00332-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 03/07/2021] [Accepted: 03/24/2021] [Indexed: 02/02/2023]
Abstract
Post-translational modifications of histones by histone demethylases plays an important role in the regulation of gene transcription and are implicated in cancers. Castrate resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. However, the role of KDM1B involved in next generation anti-enzalutamide resistance and the mechanisms of KDM1B regulation are poorly defined. Here, we show that KDM1B is upregulated and correlated with prostate cancer progression and poor prognosis. Downregulation of miR-215 is correlated with overexpression of KDM1B in enzalutamide-resistant prostate cancer cells, which promotes AR-dependent AGR2 transcription and regulates the sensitivity to next generation AR-targeted therapy. Inhibition of KDM1B significantly inhibits prostate tumor growth and improves enzalutamide treatments through AGR2 suppression. Our studies demonstrate inhibition of KDM1B can offer a viable therapeutic option to overcome enzalutamide resistance in tumors with deregulated miR-215-KDM1B-AR-AGR2 signaling axis.
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Affiliation(s)
- Donge Tang
- Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Department of Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, Guangdong, China
| | - Jiaxi He
- Department of Pathology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Yong Dai
- Department of Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, Guangdong, China
| | - Xinyan Geng
- Department of Biochemistry, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Qixin Leng
- Department of Pathology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Haowu Jiang
- Department of Anesthesiology and Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA
| | - Rui Sun
- Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - Songhui Xu
- Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
- Department of Pathology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
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Musfee FI, Oluwafemi OO, Agopian A, Hakonarson H, Goldmuntz E, Mitchell LE. Maternal Effect Genes as Risk Factors for Congenital Heart Defects. HGG ADVANCES 2022; 3:100098. [PMID: 35345810 PMCID: PMC8957044 DOI: 10.1016/j.xhgg.2022.100098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/04/2022] [Indexed: 11/09/2022] Open
Abstract
Maternal effect genes (MEGs) encode factors (e.g., RNA) in the oocyte that control embryonic development prior to activation of the embryonic genome. Over 80 mammalian MEGs have been identified, including several that have been associated with phenotypes in humans. Maternal variation in MEGs is associated with a range of adverse outcomes, which, in humans, include hydatidiform moles, zygotic cleavage failure, and offspring with multi-locus imprinting disorders. In addition, data from both animal models and humans suggest that the MEGs may be associated with structural birth defects such as congenital heart defects (CHDs). To further investigate the association between MEGs and CHDs, we conducted gene-level and gene-set analyses of known mammalian MEGs (n = 82) and two common groups of CHDs: conotruncal heart defects and left ventricular outflow tract defects. We identified 14 candidate CHD-related MEGs. These 14 MEGs include three (CDC20, KHDC3L, and TRIP13) of the 11 known human MEGs, as well as one (DNMT3A) of the eight MEGs that have been associated with structural birth defects in animal models. Our analyses add to the growing evidence that MEGs are associated with structural birth defects, in particular CHDs. Given the large proportion of individuals with structural birth defects for whom etiology of their condition is unknown, further investigations of MEGs as potential risk factors for structural birth defects are strongly warranted.
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Abstract
Maternal effect genes (MEGs) encode factors (e.g., RNA) that are present in the oocyte and required for early embryonic development. Hence, while these genes and gene products are of maternal origin, their phenotypic consequences result from effects on the embryo. The first mammalian MEGs were identified in the mouse in 2000 and were associated with early embryonic loss in the offspring of homozygous null females. In humans, the first MEG was identified in 2006, in women who had experienced a range of adverse reproductive outcomes, including hydatidiform moles, spontaneous abortions, and stillbirths. Over 80 mammalian MEGs have subsequently been identified, including several that have been associated with phenotypes in humans. In general, pathogenic variants in MEGs or the absence of MEG products are associated with a spectrum of adverse outcomes, which in humans range from zygotic cleavage failure to offspring with multi-locus imprinting disorders. Although less established, there is also evidence that MEGs are associated with structural birth defects (e.g., craniofacial malformations, congenital heart defects). This review provides an updated summary of mammalian MEGs reported in the literature through early 2021, as well as an overview of the evidence for a link between MEGs and structural birth defects.
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Genetic Studies on Mammalian DNA Methyltransferases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1389:111-136. [PMID: 36350508 PMCID: PMC9815518 DOI: 10.1007/978-3-031-11454-0_5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Cytosine methylation at the C5-position-generating 5-methylcytosine (5mC)-is a DNA modification found in many eukaryotic organisms, including fungi, plants, invertebrates, and vertebrates, albeit its levels vary greatly in different organisms. In mammals, cytosine methylation occurs predominantly in the context of CpG dinucleotides, with the majority (60-80%) of CpG sites in their genomes being methylated. DNA methylation plays crucial roles in the regulation of chromatin structure and gene expression and is essential for mammalian development. Aberrant changes in DNA methylation and genetic alterations in enzymes and regulators involved in DNA methylation are associated with various human diseases, including cancer and developmental disorders. In mammals, DNA methylation is mediated by two families of DNA methyltransferases (Dnmts), namely Dnmt1 and Dnmt3 proteins. Over the last three decades, genetic manipulations of these enzymes, as well as their regulators, in mice have greatly contributed to our understanding of the biological functions of DNA methylation in mammals. In this chapter, we discuss genetic studies on mammalian Dnmts, focusing on their roles in embryogenesis, cellular differentiation, genomic imprinting, and human diseases.
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KDM1A Identified as a Potential Oncogenic Driver and Prognostic Biomarker via Multi-Omics Analysis. CANADIAN JOURNAL OF INFECTIOUS DISEASES AND MEDICAL MICROBIOLOGY 2021; 2021:4668565. [PMID: 34925656 PMCID: PMC8677413 DOI: 10.1155/2021/4668565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 11/12/2021] [Indexed: 11/17/2022]
Abstract
Background Lysine-specific demethylase 1A (KDM1A) is a histone demethylation enzyme and a crucial epigenetic factor for multiple pathological pathways that mediate carcinogenesis and immunogenicity. Although increasing evidence supposes the association between KDM1A and cancers, no systematic multi-omics analysis of KDM1A is available. Methods We systematically evaluated the KDM1A expression of various cancer and normal tissues and the unique relationship between KDM1A expression and prognosis of cancer cases based on The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. The genetic variations, phosphorylation, and DNA methylation of KDM1A were analyzed via various tools. We further analyzed the correlation of KDM1A expression and fibroblasts and immune cell infiltration score of TCGA samples via TIMER2.0. Results KDM1A was highly expressed in 17 types of total 33 cancers, while it expressed low levels in only 4 cancers. High KDM1A expression was associated with worse survival status in various cancers. KDM1A expression was positively correlated with the cancer-associated fibroblasts and myeloid-derived suppressor cells infiltration levels in most cancer types. Additionally, KDM1A in most cancer types was negatively correlated with Th1 cell infiltration and positively correlated with Th2 cells. Moreover, spliceosome, cell cycle, and RNA transport pathways were involved in the functional mechanisms of KDM1A via enrichment analysis. Conclusions Our study describes the epigenetic factor KDM1A as an oncogene and prognostic biomarker. Our findings provide valuable guidance for further analysis of KDM1A function in pathogenesis and potential clinical treatment.
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Li Z, Qin T, Li Z, Zhao X, Zhang X, Zhao T, Yang N, Miao J, Ma J, Zhang Z. Discovery of quinazoline derivatives as a novel class of potent and in vivo efficacious LSD1 inhibitors by drug repurposing. Eur J Med Chem 2021; 225:113778. [PMID: 34416665 DOI: 10.1016/j.ejmech.2021.113778] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/29/2021] [Accepted: 08/12/2021] [Indexed: 01/09/2023]
Abstract
Histone lysine-specific demethylase 1 (LSD1) is an important epigenetic modulator, and is implicated in malignant transformation and tumor pathogenesis in different ways. Therefore, the inhibition of LSD1 provides an attractive therapeutic target for cancer therapy. Based on drug repurposing strategy, we screened our in-house chemical library toward LSD1, and found that the EGFR inhibitor erlotinib, an FDA-approved drug for lung cancer, possessed low potency against LSD1 (IC50 = 35.80 μM). Herein, we report our further medicinal chemistry effort to obtain a highly water-soluble erlotinib analog 5k (>100 mg/mL) with significantly enhanced inhibitory activity against LSD1 (IC50 = 0.69 μM) as well as higher specificity. In MGC-803 cells, 5k suppressed the demethylation of LSD1, indicating its cellular activity against the enzyme. In addition, 5k had a remarkable capacity to inhibit colony formation, suppress migration and induce apoptosis of MGC803 cells. Furthermore, in MGC-803 xenograft mouse model, 5k treatment resulted in significant reduction in tumor size by 81.6% and 96.1% at dosages of 40 and 80 mg/kg/d, respectively. Our findings indicate that erlotinib-based analogs provide a novel structural set of LSD1 inhibitors with potential for further investigation, and may serve as novel candidates for the treatment of LSD1-overexpressing cancers.
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Affiliation(s)
- Zhonghua Li
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
| | - Tingting Qin
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Zhongrui Li
- School of Pharmacy, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Xuan Zhao
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Xinhui Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Taoqian Zhao
- Department of Chemistry, National University of Singapore, 117543, Singapore
| | - Nian Yang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Jinxin Miao
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
| | - Jinlian Ma
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
| | - Zhenqiang Zhang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
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Wang G, Han JJ. Connections between metabolism and epigenetic modifications in cancer. MEDICAL REVIEW (BERLIN, GERMANY) 2021; 1:199-221. [PMID: 37724300 PMCID: PMC10388788 DOI: 10.1515/mr-2021-0015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/19/2021] [Indexed: 09/20/2023]
Abstract
How cells sense and respond to environmental changes is still a key question. It has been identified that cellular metabolism is an important modifier of various epigenetic modifications, such as DNA methylation, histone methylation and acetylation and RNA N6-methyladenosine (m6A) methylation. This closely links the environmental nutrient availability to the maintenance of chromatin structure and gene expression, and is crucial to regulate cellular homeostasis, cell growth and differentiation. Cancer metabolic reprogramming and epigenetic alterations are widely observed, and facilitate cancer development and progression. In cancer cells, oncogenic signaling-driven metabolic reprogramming modifies the epigenetic landscape via changes in the key metabolite levels. In this review, we briefly summarized the current evidence that the abundance of key metabolites, such as S-adenosyl methionine (SAM), acetyl-CoA, α-ketoglutarate (α-KG), 2-hydroxyglutarate (2-HG), uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) and lactate, affected by metabolic reprogramming plays an important role in dynamically regulating epigenetic modifications in cancer. An improved understanding of the roles of metabolic reprogramming in epigenetic regulation can contribute to uncover the underlying mechanisms of metabolic reprogramming in cancer development and identify the potential targets for cancer therapies.
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Affiliation(s)
- Guangchao Wang
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, China
| | - Jingdong J. Han
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, China
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Zeng TB, Pierce N, Liao J, Singh P, Lau K, Zhou W, Szabó PE. EHMT2 suppresses the variation of transcriptional switches in the mouse embryo. PLoS Genet 2021; 17:e1009908. [PMID: 34793451 PMCID: PMC8601470 DOI: 10.1371/journal.pgen.1009908] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 10/23/2021] [Indexed: 12/13/2022] Open
Abstract
EHMT2 is the main euchromatic H3K9 methyltransferase. Embryos with zygotic, or maternal mutation in the Ehmt2 gene exhibit variable developmental delay. To understand how EHMT2 prevents variable developmental delay we performed RNA sequencing of mutant and somite stage-matched normal embryos at 8.5–9.5 days of gestation. Using four-way comparisons between delayed and normal embryos we clarified what it takes to be normal and what it takes to develop. We identified differentially expressed genes, for example Hox genes that simply reflected the difference in developmental progression of wild type and the delayed mutant uterus-mate embryos. By comparing wild type and zygotic mutant embryos along the same developmental window we detected a role of EHMT2 in suppressing variation in the transcriptional switches. We identified transcription changes where precise switching during development occurred only in the normal but not in the mutant embryo. At the 6-somite stage, gastrulation-specific genes were not precisely switched off in the Ehmt2−/− zygotic mutant embryos, while genes involved in organ growth, connective tissue development, striated muscle development, muscle differentiation, and cartilage development were not precisely switched on. The Ehmt2mat−/+ maternal mutant embryos displayed high transcriptional variation consistent with their variable survival. Variable derepression of transcripts occurred dominantly in the maternally inherited allele. Transcription was normal in the parental haploinsufficient wild type embryos despite their delay, consistent with their good prospects. Global profiling of transposable elements revealed EHMT2 targeted DNA methylation and suppression at LTR repeats, mostly ERVKs. In Ehmt2−/− embryos, transcription over very long distances initiated from such misregulated ‘driver’ ERVK repeats, encompassing a multitude of misexpressed ‘passenger’ repeats. In summary, EHMT2 reduced transcriptional variation of developmental switch genes and developmentally switching repeat elements at the six-somite stage embryos. These findings establish EHMT2 as a suppressor of transcriptional and developmental variation at the transition between gastrulation and organ specification. Developmental variation is the property of normal development, and its regulation is poorly understood. Variable developmental delay is found in embryos that carry mutations of epigenetic modifiers, suggesting a role of chromatin in controlling developmental delay and its variable nature. We analyzed a genetic series of mutations and found that EHMT2 suppresses variation of developmental delay and also suppresses the variation of transcriptional switches at the transition between gastrulation and organ specification.
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Affiliation(s)
- Tie-Bo Zeng
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan, United States of America
| | - Nicholas Pierce
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan, United States of America
| | - Ji Liao
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan, United States of America
| | - Purnima Singh
- Division of Molecular and Cellular Biology, City of Hope Cancer Center, Duarte, California, United States of America
| | - Kin Lau
- Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, Michigan, United States of America
| | - Wanding Zhou
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan, United States of America
| | - Piroska E. Szabó
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan, United States of America
- * E-mail:
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Qin Z, Li Z, Yang S, Wang F, Gao T, Tao W, Zhou L, Wang D, Sun L. Genome-wide identification, evolution of histone lysine demethylases (KDM) genes and their expression during gonadal development in Nile tilapia. Comp Biochem Physiol B Biochem Mol Biol 2021; 257:110674. [PMID: 34624518 DOI: 10.1016/j.cbpb.2021.110674] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 12/16/2022]
Abstract
Histone lysine demethylases (KDM) are responsible for histone demethylation and are involved in gene expression regulation. Previous studies have shown that histone lysine demethylation plays an important role in gonadal development of vertebrates. The KDM family consists of eight subfamilies, i.e., kdm1, kdm2, kdm3, kdm4, kdm5, kdm6, kdm7 and JmjC-only subfamily. In this study, 13 to 63 KDM genes in 23 representative species were identified based on the available version of genome assembly. Phylogenetic relationships, domain architecture, and synteny of these genes were comprehensively analyzed and the results suggested KDM genes probably originated from the early diverging metazoan and significantly expanded in vertebrates with multiple whole genome duplication, especially in the third-round whole genome duplication (3R-WGD) and polyploidization of teleosts. The subfamilies of kdm2, kdm3, kdm4, kdm5, kdm6 and kdm7 were duplicated with 1R-2R events, and duplicates of kdm2a, kdm4a, kdm5b and kdm6b were resulted from 3R-WGD. Based on transcriptome data, the KDM genes were found to be dominantly expressed in the ovary and testis. More than 80% of KDM genes displayed sexual dimorphic expression, with 15 genes dominantly expressed in ovaries, and 12 genes dominantly expressed in testes. Importantly, from transcriptome data, qRT-PCR and fluorescence in situ hybridization during sex reversal, genes with higher expression in ovary than testis, such as kdm1b and two JmjC-only subfamily members hspbap1 and riox1, were downregulated, while other genes, such as kdm3c, kdm5bb, kdm6ba, kdm6bb and kdm7b, with higher expression in testis than ovary, were upregulated in ovotestis, indicating these genes play critical roles in the gonadal development and sex reversal. This study provided new insights into the evolution of the KDM genes and a fundamental clue for understanding their important roles in sex differentiation and gonadal development in teleosts.
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Affiliation(s)
- Zuliang Qin
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Sciences, Southwest University, 400715 Chongqing, PR China
| | - Zhiqiang Li
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Sciences, Southwest University, 400715 Chongqing, PR China
| | - Shuangyi Yang
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Sciences, Southwest University, 400715 Chongqing, PR China
| | - Feilong Wang
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Sciences, Southwest University, 400715 Chongqing, PR China
| | - Tian Gao
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Sciences, Southwest University, 400715 Chongqing, PR China
| | - Wenjing Tao
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Sciences, Southwest University, 400715 Chongqing, PR China
| | - Linyan Zhou
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Sciences, Southwest University, 400715 Chongqing, PR China
| | - Deshou Wang
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Sciences, Southwest University, 400715 Chongqing, PR China
| | - Lina Sun
- Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Sciences, Southwest University, 400715 Chongqing, PR China.
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Bilmez Y, Talibova G, Ozturk S. Dynamic changes of histone methylation in mammalian oocytes and early embryos. Histochem Cell Biol 2021; 157:7-25. [PMID: 34599660 DOI: 10.1007/s00418-021-02036-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2021] [Indexed: 12/18/2022]
Abstract
Histone methylation is a key epigenetic mechanism and plays a major role in regulating gene expression during oocyte maturation and early embryogenesis. This mechanism can be briefly defined as the process by which methyl groups are transferred to lysine and arginine residues of histone tails extending from nucleosomes. While methylation of the lysine residues is catalyzed by histone lysine methyltransferases (KMTs), protein arginine methyltransferases (PRMTs) add methyl groups to the arginine residues. When necessary, the added methyl groups can be reversibly removed by histone demethylases (HDMs) by a process called histone demethylation. The spatiotemporal regulation of methylation and demethylation in histones contributes to modulating the expression of genes required for proper oocyte maturation and early embryonic development. In this review, we comprehensively evaluate and discuss the functional importance of dynamic histone methylation in mammalian oocytes and early embryos, regulated by KMTs, PRMTs, and HDMs.
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Affiliation(s)
- Yesim Bilmez
- Department of Histology and Embryology, Akdeniz University School of Medicine, Campus, 07070, Antalya, Turkey
| | - Gunel Talibova
- Department of Histology and Embryology, Akdeniz University School of Medicine, Campus, 07070, Antalya, Turkey
| | - Saffet Ozturk
- Department of Histology and Embryology, Akdeniz University School of Medicine, Campus, 07070, Antalya, Turkey.
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