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Xu S, Long K, Wang T, Zhu Y, Zhang Y, Wang W. Opto-Epigenetic Regulation of Histone Arginine Asymmetric Dimethylation via Type I Protein Arginine Methyltransferase Inhibition. J Med Chem 2025; 68:4373-4381. [PMID: 39961800 DOI: 10.1021/acs.jmedchem.4c02199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2025]
Abstract
Histone arginine asymmetric dimethylation, which is mainly catalyzed by type I protein arginine methyltransferases (PRMTs), is involved in broad biological and pathological processes. Recently, several type I PRMT inhibitors, such as MS023, have been developed to reverse the histone arginine dimethylation status in tumor cells, but extensive inhibition of type I PRMTs may cause side effects in normal tissues. Herein, we designed a photoactivatable MS023 prodrug (C-MS023) to achieve spatiotemporal inhibition of histone arginine asymmetric dimethylation. In vitro studies showed that C-MS023 exhibited reduced potency in inhibiting type I PRMTs. Importantly, visible light irradiation at 420 nm could trigger the photolysis of the prodrug, thereby liberating MS023 for effective downregulation of histone arginine asymmetric dimethylation and DNA replication-related transcriptomic activities. This opto-epigenetic small-molecule prodrug potentially aids in further research into the pathophysiological functions of type I PRMTs and the development of targeted epigenetic therapeutics.
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Affiliation(s)
- Shuting Xu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong 999077, China
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
- Laboratory of Molecular Engineering and Nanomedicine, Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong 999077, China
| | - Kaiqi Long
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong 999077, China
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
- Laboratory of Molecular Engineering and Nanomedicine, Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong 999077, China
| | - Tianyi Wang
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong 999077, China
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
- Laboratory of Molecular Engineering and Nanomedicine, Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong 999077, China
| | - Yangyang Zhu
- The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, P. R. China
- School of Biomedical Sciences and Engineering, National Engineering Research Center for Tissue Restoration and Reconstruction and Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou 510006, P. R. China
| | - Yunjiao Zhang
- The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, P. R. China
- School of Biomedical Sciences and Engineering, National Engineering Research Center for Tissue Restoration and Reconstruction and Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou 510006, P. R. China
| | - Weiping Wang
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong 999077, China
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
- Laboratory of Molecular Engineering and Nanomedicine, Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong 999077, China
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Wagih N, Abdel-Rahman IM, El-Koussi NA, El-Din A Abuo-Rahma G. Anticancer benzimidazole derivatives as inhibitors of epigenetic targets: a review article. RSC Adv 2025; 15:966-1010. [PMID: 39807197 PMCID: PMC11726184 DOI: 10.1039/d4ra05014b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 12/11/2024] [Indexed: 01/16/2025] Open
Abstract
Cancer is one of the leading causes of morbidity and mortality worldwide. One of the primary causes of cancer development and progression is epigenetic dysregulation, which is a heritable modification that alters gene expression without changing the DNA sequence. Therefore, targeting these epigenetic changes has emerged as a promising therapeutic strategy. Benzimidazole derivatives have gained attention for their potent epigenetic modulatory effects as they interact with various epigenetic targets, including DNA methyltransferases, histone deacetylases and histone methyltransferases. This review provides a comprehensive overview of benzimidazole derivatives that inhibit different acetylation and methylation reader, writer and eraser epigenetic targets. Herein, we emphasize the therapeutic potential of these compounds in developing targeted, less toxic cancer therapies. Presently, some promising benzimidazole derivatives have entered clinical trials and shown great advancements in the fields of hematological and solid malignancy therapies. Accordingly, we highlight the recent advancements in benzimidazole research as epigenetic agents that could pave the way for designing new multi-target drugs to overcome resistance and improve clinical outcomes for cancer patients. This review can help researchers in designing new anticancer benzimidazole derivatives with better properties.
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Affiliation(s)
- Nardin Wagih
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University New Minia 61111 Egypt
| | - Islam M Abdel-Rahman
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University New Minia 61111 Egypt
| | - Nawal A El-Koussi
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University New Minia 61111 Egypt
- Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University 71526 Assiut Egypt
| | - Gamal El-Din A Abuo-Rahma
- Medicinal Chemistry Department, Faculty of Pharmacy, Minia University 61519 Minia Egypt
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University New Minia 61111 Egypt
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3
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Su XM, Yuan DY, Liu N, Zhang ZC, Yang M, Li L, Chen S, Zhou Y, He XJ. ALFIN-like proteins link histone H3K4me3 to H2A ubiquitination and coordinate diverse chromatin modifications in Arabidopsis. MOLECULAR PLANT 2025; 18:130-150. [PMID: 39668562 DOI: 10.1016/j.molp.2024.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 11/15/2024] [Accepted: 12/08/2024] [Indexed: 12/14/2024]
Abstract
Trimethylation of histone H3K4 (H3K4me3) is widely distributed at numerous actively transcribed protein-coding genes throughout the genome. However, the interplay between H3K4me3 and other chromatin modifications in plants remains poorly understood. In this study, we show that the Arabidopsis thaliana ALFIN-LIKE (AL) proteins contain a C-terminal PHD finger capable of binding to H3K4me3 and a PHD-associated AL (PAL) domain that interacts with components of the Polycomb repressive complex 1, thereby facilitating H2A ubiquitination (H2Aub) at H3K4me3-enriched genes throughout the genome. Furthermore, we demonstrate that loss of function of SDG2, encoding a key histone H3K4 methyltransferase, leads to a reduction in H3K4me3 level, which subsequently causes a genome-wide decrease in H2Aub, revealing a strong association between H3K4me3 and H2Aub. Finally, we discover that the PAL domain of AL proteins interacts with various other chromatin-related proteins or complexes, including those involved in regulating H2A.Z deposition, H3K27me3 demethylation, histone deacetylation, and chromatin accessibility. Our genome-wide analysis suggests that the AL proteins play a crucial role in coordinating H3K4me3 with multiple other chromatin modifications across the genome.
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Affiliation(s)
- Xiao-Min Su
- College of Life Sciences, Beijing Normal University, Beijing, 100875, China; National Institute of Biological Sciences, Beijing 102206, China
| | - Dan-Yang Yuan
- National Institute of Biological Sciences, Beijing 102206, China
| | - Na Liu
- National Institute of Biological Sciences, Beijing 102206, China
| | - Zhao-Chen Zhang
- National Institute of Biological Sciences, Beijing 102206, China
| | - Minqi Yang
- State Key Laboratory of Protein and Plant Gene Research, School of Advanced Agricultural Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
| | - Lin Li
- National Institute of Biological Sciences, Beijing 102206, China
| | - She Chen
- National Institute of Biological Sciences, Beijing 102206, China
| | - Yue Zhou
- State Key Laboratory of Protein and Plant Gene Research, School of Advanced Agricultural Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
| | - Xin-Jian He
- College of Life Sciences, Beijing Normal University, Beijing, 100875, China; National Institute of Biological Sciences, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 10084, China.
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4
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Mella C, Tsarouhas P, Brockwell M, Ball HC. The Role of Chronic Inflammation in Pediatric Cancer. Cancers (Basel) 2025; 17:154. [PMID: 39796780 PMCID: PMC11719864 DOI: 10.3390/cancers17010154] [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: 12/04/2024] [Revised: 12/31/2024] [Accepted: 01/01/2025] [Indexed: 01/13/2025] Open
Abstract
Inflammation plays a crucial role in wound healing and the host immune response following pathogenic invasion. However, unresolved chronic inflammation can result in tissue fibrosis and genetic alterations that contribute to the pathogenesis of human diseases such as cancer. Recent scientific advancements exploring the underlying mechanisms of malignant cellular transformations and cancer progression have exposed significant disparities between pediatric and adult-onset cancers. For instance, pediatric cancers tend to have lower mutational burdens and arise in actively developing tissues, where cell-cycle dysregulation leads to gene, chromosomal, and fusion gene development not seen in adult-onset counterparts. As such, scientific findings in adult cancers cannot be directly applied to pediatric cancers, where unique mutations and inherent etiologies remain poorly understood. Here, we review the role of chronic inflammation in processes of genetic and chromosomal instability, the tumor microenvironment, and immune response that result in pediatric tumorigenesis transformation and explore current and developing therapeutic interventions to maintain and/or restore inflammatory homeostasis.
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Affiliation(s)
- Christine Mella
- Division of Hematology Oncology, Akron Children’s Hospital, One Perkins Square, Akron, OH 44308, USA;
| | - Panogiotis Tsarouhas
- Department of Biology, The University of Akron, 302 Buchtel Common, Akron, OH 44325, USA;
| | - Maximillian Brockwell
- College of Medicine, Northeast Ohio Medical University, 4029 State Route 44, Rootstown, OH 44272, USA;
| | - Hope C. Ball
- Division of Hematology Oncology, Akron Children’s Hospital, One Perkins Square, Akron, OH 44308, USA;
- College of Medicine, Northeast Ohio Medical University, 4029 State Route 44, Rootstown, OH 44272, USA;
- Rebecca D. Considine Research Institute, Akron Children’s Hospital, One Perkins Square, Akron, OH 44308, USA
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Cao Q, Xu W, Chen X, Luo G, Reinach PS, Yan D. PRMT1-Mediated Arginine Methylation Promotes Corneal Epithelial Wound Healing via Epigenetic Regulation of ANXA3. Invest Ophthalmol Vis Sci 2025; 66:22. [PMID: 39786757 PMCID: PMC11725987 DOI: 10.1167/iovs.66.1.22] [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: 07/25/2024] [Accepted: 12/15/2024] [Indexed: 01/12/2025] Open
Abstract
Purpose Protein arginine methyltransferase 1 (PRMT1) is an integral constituent of numerous cellular processes. However, its role in corneal epithelial wound healing (CEWH) remains unclear. This study investigates the impact of PRMT1 on cellular mechanisms underlying corneal epithelial repair and its potential to improve wound healing outcomes. Methods The murine CEWH model was established using an Alger brush. Corneal epithelial-specific Prmt1 knockout mice were generated using the Cre-lox system. Quantitative reverse transcription polymerase chain reaction and Western blot analyses determined the expression of candidate genes at mRNA and protein expression levels. Human corneal epithelial cells (HCECs) were transfected with siRNA using Lipofectamine RNAiMAX or infected with lentivirus to precisely alter the expression of PRMT1 or Annexin A3 (ANXA3). EdU and a scratch wound-healing assay evaluated the effects of PRMT1 or ANXA3 on HCEC proliferation and migration, respectively. Rescue experiment and chromatin immunoprecipitation assay validate the correlation between PRMT1 and ANXA3. Results Prmt1 is significantly upregulated during CEWH, accompanied by an elevated global arginine methylation level. Knockdown of PRMT1 in HCECs or in vivo knockout impairs cell proliferation, migration, and the CEWH process. Furthermore, ANXA3 was identified as a critical target of PRMT1, with PRMT1 enhancing ANXA3 expression through histone arginine methylation at its promoter region, establishing a causal correlation between them. Moreover, PRMT1 can modulate the NF-κB and JNK signaling pathways via ANXA3. Conclusions PRMT1 is a critical epigenetic regulator in CEWH, promoting wound healing by upregulating ANXA3 via histone arginine methylation. These findings highlight the potential of targeting PRMT1 to enhance corneal epithelial repair.
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Affiliation(s)
- Qiongjie Cao
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Wenji Xu
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Xiaoyan Chen
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Guangying Luo
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Peter S. Reinach
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Dongsheng Yan
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
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6
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Gupta S, Verma M, Kadumuri RV, Chutani N, Khan MIK, Chavali S, Dhayalan A. The uncharacterized protein ZNF200 interacts with PRMT3 and aids its stability and nuclear translocation. Biochem J 2024; 481:1723-1740. [PMID: 39513743 DOI: 10.1042/bcj20240476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 11/06/2024] [Accepted: 11/08/2024] [Indexed: 11/15/2024]
Abstract
Protein arginine methyltransferase 3 (PRMT3), a type I arginine methyltransferase is localized predominantly in the cytoplasm and regulates different cellular functions. Nevertheless, PRMT3 also exhibits regulatory functions in the nucleus by interacting with the liver X receptor alpha (LXRα) and catalyzes asymmetric dimethylation modifications at arginine 3 of histone 4 (H4R3me2a). However, very little is known about the regulation of the versatile global regulator PRMT3 and how PRMT3 is translocated to the nucleus. In this study, we identified ZNF200, a hitherto uncharacterized protein, as a potential binding partner of PRMT3 through yeast two-hybrid screening. We confirmed the interaction of PRMT3 with ZNF200 using immunoprecipitation and in vitro pull-down experiments. GST pull-down experiments and molecular docking studies revealed that the N-terminal zinc finger domain of PRMT3 binds to the C-terminal zinc finger regions of ZNF200. Furthermore, the evolutionary conservation of the Znf domain of PRMT3 correlates with the emergence of ZNF200 in mammals. We found that ZNF200 stabilizes PRMT3 by inhibiting its proteasomal degradation. ZNF200, a nuclear-predominant protein, promotes the nuclear translocation of PRMT3, leading to the global increase of H4R3me2a modifications. These findings imply that ZNF200 is a critical regulator of the steady-state levels and nuclear and epigenetic functions of PRMT3.
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Affiliation(s)
- Somlee Gupta
- Department of Biotechnology, Pondicherry University, Puducherry 605 014, India
| | - Mamta Verma
- Department of Biotechnology, Pondicherry University, Puducherry 605 014, India
| | - Rajashekar Varma Kadumuri
- Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati 517 507, Andhra Pradesh, India
| | - Namita Chutani
- Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati 517 507, Andhra Pradesh, India
| | - Mohd Imran K Khan
- Department of Biotechnology, Pondicherry University, Puducherry 605 014, India
| | - Sreenivas Chavali
- Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati 517 507, Andhra Pradesh, India
| | - Arunkumar Dhayalan
- Department of Biotechnology, Pondicherry University, Puducherry 605 014, India
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7
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Zhou L, Zhao X, Sun J, Zou K, Huang X, Yu L, Wu M, Wang Y, Li X, Yi W. Mina53 demethylates histone H4 arginine 3 asymmetric dimethylation to regulate neural stem/progenitor cell identity. Nat Commun 2024; 15:10227. [PMID: 39587091 PMCID: PMC11589143 DOI: 10.1038/s41467-024-54680-6] [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: 10/09/2023] [Accepted: 11/18/2024] [Indexed: 11/27/2024] Open
Abstract
Arginine methylation of histones plays a critical role in regulating gene expression. The writers (methyltransferases) and readers of methylarginine marks are well-known, but the erasers-arginine demethylases-remain mysterious. Here we identify Myc-induced nuclear antigen 53 (Mina53), a jumonji C domain containing protein, as an arginine demethylase for removing asymmetric di-methylation at arginine 3 of histone H4 (H4R3me2a). Using a photoaffinity capture method, we first identify Mina53 as an interactor of H4R3me2a. Biochemical assays in vitro and in cells characterize the arginine demethylation activity of Mina53. Molecular dynamics simulations provide further atomic-level evidence that Mina53 acts on H4R3me2a. In a transgenic mouse model, specific Mina53 deletion in neural stem/progenitor cells prevents H4R3me2a demethylation at distinct genes clusters, dysregulating genes important for neural stem/progenitor cell proliferation and differentiation, and consequently impairing the cognitive function of mice. Collectively, we identify Mina53 as a bona fide H4R3me2a eraser, expanding the understanding of epigenetic gene regulation.
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Affiliation(s)
- Lixiao Zhou
- Departments of Biochemistry and Biophysics, College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Xingsen Zhao
- Institute of Biotechnology, Xianghu Laboratory, Hangzhou, China
| | - Jie Sun
- Departments of Biochemistry and Biophysics, College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Kun Zou
- Department of Chemistry, School of Science, Westlake University, Hangzhou, China
| | - Xiaoli Huang
- The Children's Hospital, National Clinical Research Center for Children Health, The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China
| | - Liyang Yu
- Departments of Biochemistry and Biophysics, College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Mingxuan Wu
- Department of Chemistry, School of Science, Westlake University, Hangzhou, China
| | - Yong Wang
- Departments of Biochemistry and Biophysics, College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Xuekun Li
- The Children's Hospital, National Clinical Research Center for Children Health, The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China.
- Cancer Center, Zhejiang University, Hangzhou, China.
| | - Wen Yi
- Departments of Biochemistry and Biophysics, College of Life Sciences, Zhejiang University, Hangzhou, China.
- Cancer Center, Zhejiang University, Hangzhou, China.
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8
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Lowe TL, Valencia DA, Velasquez VE, Quinlan ME, Clarke SG. Methylation and phosphorylation of formin homology domain proteins (Fhod1 and Fhod3) by protein arginine methyltransferase 7 (PRMT7) and Rho kinase (ROCK1). J Biol Chem 2024; 300:107857. [PMID: 39368550 PMCID: PMC11584945 DOI: 10.1016/j.jbc.2024.107857] [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: 04/08/2024] [Revised: 09/13/2024] [Accepted: 09/26/2024] [Indexed: 10/07/2024] Open
Abstract
Protein post-translational modifications (PTMs) can regulate biological processes by altering an amino acid's bulkiness, charge, and hydrogen bonding interactions. Common modifications include phosphorylation, methylation, acetylation, and ubiquitylation. Although a primary focus of studying PTMs is understanding the effects of a single amino acid modification, the possibility of additional modifications increases the complexity. For example, substrate recognition motifs for arginine methyltransferases and some serine/threonine kinases overlap, leading to potential enzymatic crosstalk. In this study we have shown that the human family of formin homology domain-containing proteins (Fhods) contain a substrate recognition motif specific for human protein arginine methyltransferase 7 (PRMT7). In particular, PRMT7 methylates two arginine residues in the diaphanous autoinhibitory domain (DAD) of the family of Fhod proteins: R1588 and/or R1590 of Fhod3 isoform 4. Additionally, we confirmed that S1589 and S1595 in the DAD domain of Fhod3 can be phosphorylated by Rho/ROCK1 kinase. Significantly, we have determined that if S1589 is phosphorylated then PRMT7 cannot subsequently methylate R1588 or R1590. In contrast, if R1588 or R1590 of Fhod3 is methylated then ROCK1 phosphorylation activity is only slightly affected. Finally, we show that the interaction of the N-terminal DID domain can also inhibit the methylation of the DAD domain. Taken together these results suggest that the family of Fhod proteins, potential in vivo substrates for PRMT7, might be regulated by a combination of methylation and phosphorylation.
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Affiliation(s)
- Troy L Lowe
- Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA; Molecular Biology Institute, University of California - Los Angeles, Los Angeles, California, USA
| | - Dylan A Valencia
- Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA; Molecular Biology Institute, University of California - Los Angeles, Los Angeles, California, USA
| | - Vicente E Velasquez
- Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA
| | - Margot E Quinlan
- Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA; Molecular Biology Institute, University of California - Los Angeles, Los Angeles, California, USA
| | - Steven G Clarke
- Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA; Molecular Biology Institute, University of California - Los Angeles, Los Angeles, California, USA.
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Barré-Villeneuve C, Azevedo-Favory J. R-Methylation in Plants: A Key Regulator of Plant Development and Response to the Environment. Int J Mol Sci 2024; 25:9937. [PMID: 39337424 PMCID: PMC11432338 DOI: 10.3390/ijms25189937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/11/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Although arginine methylation (R-methylation) is one of the most important post-translational modifications (PTMs) conserved in eukaryotes, it has not been studied to the same extent as phosphorylation and ubiquitylation. Technical constraints, which are in the process of being resolved, may partly explain this lack of success. Our knowledge of R-methylation has recently evolved considerably, particularly in metazoans, where misregulation of the enzymes that deposit this PTM is implicated in several diseases and cancers. Indeed, the roles of R-methylation have been highlighted through the analyses of the main actors of this pathway: the PRMT writer enzymes, the TUDOR reader proteins, and potential "eraser" enzymes. In contrast, R-methylation has been much less studied in plants. Even so, it has been shown that R-methylation in plants, as in animals, regulates housekeeping processes such as transcription, RNA silencing, splicing, ribosome biogenesis, and DNA damage. R-methylation has recently been highlighted in the regulation of membrane-free organelles in animals, but this role has not yet been demonstrated in plants. The identified R-met targets modulate key biological processes such as flowering, shoot and root development, and responses to abiotic and biotic stresses. Finally, arginine demethylases activity has mostly been identified in vitro, so further studies are needed to unravel the mechanism of arginine demethylation.
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Affiliation(s)
- Clément Barré-Villeneuve
- Crop Biotechnics, Department of Biosystems, KU Leuven, 3000 Leuven, Belgium
- KU Leuven Plant Institute (LPI), KU Leuven, 3000 Leuven, Belgium
| | - Jacinthe Azevedo-Favory
- CNRS, Laboratoire Génome et Développement des Plantes, UMR 5096, 66860 Perpignan, France
- Laboratoire Génome et Développement des Plantes, Université Perpignan Via Domitia, UMR 5096, 66860 Perpignan, France
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10
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Rehman S, Parent M, Storey KB. Histone Arginine Methylation as a Regulator of Gene Expression in the Dehydrating African Clawed Frog ( Xenopus laevis). Genes (Basel) 2024; 15:1156. [PMID: 39336747 PMCID: PMC11431520 DOI: 10.3390/genes15091156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 08/28/2024] [Accepted: 08/30/2024] [Indexed: 09/30/2024] Open
Abstract
The African clawed frog (Xenopus laevis) endures prolonged periods of dehydration while estivating underground during the dry season. Epigenetic modifications play crucial roles in regulating gene expression in response to environmental changes. The elucidation of epigenetic changes relevant to survival could serve as a basis for further studies on organ preservation under extreme stress. The current study examined the relative protein levels of key enzymes involved in the arginine methylation of histones in the liver and kidney tissues of control versus dehydrated (35 ± 1%) X. laevis through immunoblotting. Protein arginine methyltransferases (PRMT) 4, 5, and 6 showed significant protein level decreases of 35 ± 3%, 71 ± 7%, and 25 ± 5%, respectively, in the liver tissues of the dehydrated frogs relative to controls. In contrast, PRMT7 exhibited an increase of 36 ± 4%. Similarly, the methylated histone markers H3R2m2a, H3R8m2a, and H3R8m2s were downregulated by 34 ± 11%, 15 ± 4%, and 42 ± 12%, respectively, in the livers of dehydrated frogs compared to controls. By contrast, the kidneys of dehydrated frogs showed an upregulation of histone markers. H3R2m2a, H3R8m2a, H3R8m2s, and H4R3m2a were significantly increased by 126 ± 12%, 112 ± 7%, 47 ± 13%, and 13 ± 3%, respectively. These changes can play vital roles in the metabolic reorganization of X. laevis during dehydration, and are likely to increase the chances of survival. In turn, the tissue-specific regulation of the histone arginine methylation mechanism suggests the importance of epigenetic regulation in the adaptation of X. laevis for whole-body dehydration.
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Affiliation(s)
| | | | - Kenneth B. Storey
- Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; (S.R.)
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11
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Orlandini M, Bonacini A, Favero A, Secchi A, Lazzarini L, Verucchi R, Dalcanale E, Pedrini A, Sidoli S, Pinalli R. Enrichment of histone tail methylated lysine residues via cavitand-decorated magnetic nanoparticles for ultra-sensitive proteomics. Chem Sci 2024; 15:13102-13110. [PMID: 39148787 PMCID: PMC11322979 DOI: 10.1039/d4sc02076f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 07/12/2024] [Indexed: 08/17/2024] Open
Abstract
Nearly every protein in the human body is modified with post-translational modifications (PTMs). PTMs affect proteins on many levels, including their function, interaction, half-life, and localization. Specifically, for histone proteins, PTMs such as lysine methylation and acetylation play essential roles in chromatin dynamic regulations. For this reason, methods to accurately detect and quantify PTMs are of paramount importance in cell biology, biochemistry, and disease biology. Most protein modifications are sub-stoichiometric, so, to be analyzed, they need methods of enrichment, which are mostly based on antibodies. Antibodies are produced using animals, resulting in high costs, ecological concerns, significant batch variations, and ethical implications. We propose using ferromagnetic nanoparticles functionalized with synthetic receptors, namely tetraphosphonate cavitands, as a tool for selective enrichment of methylated lysines present on histone tails. Before the enrichment step, histone proteins from calf thymus were digested to facilitate the recognition process and to obtain small peptides suitable for mass analyses. Cavitands were anchored on ferromagnetic nanoparticles to easily separate the PTM-peptides of interest from the rest of the proteolytic peptides. Our approach detects more modified peptides with higher signal intensity, rivaling commercial antibodies. This chemical strategy offers a cost-effective and efficient alternative for PTM detection, potentially advancing proteomic research.
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Affiliation(s)
- Martina Orlandini
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, INSTM, UdR Parma Parco Area delle Scienze 17/A 43124 Parma Italy
| | - Alex Bonacini
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, INSTM, UdR Parma Parco Area delle Scienze 17/A 43124 Parma Italy
| | - Alessia Favero
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, INSTM, UdR Parma Parco Area delle Scienze 17/A 43124 Parma Italy
| | - Andrea Secchi
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, INSTM, UdR Parma Parco Area delle Scienze 17/A 43124 Parma Italy
| | - Laura Lazzarini
- IMEM-CNR, Institute of Materials for Electronics and Magnetism, National Research Council Parco Area delle Scienze 37/A 43124 Parma Italy
| | - Roberto Verucchi
- IMEM-CNR, Institute of Materials for Electronics and Magnetism, National Research Council, Trento Unit via alla Cascata 56/C 38123 Trento Italy
| | - Enrico Dalcanale
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, INSTM, UdR Parma Parco Area delle Scienze 17/A 43124 Parma Italy
| | - Alessandro Pedrini
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, INSTM, UdR Parma Parco Area delle Scienze 17/A 43124 Parma Italy
| | - Simone Sidoli
- Department of Biochemistry, Albert Einstein College of Medicine Bronx NY 10461 USA
| | - Roberta Pinalli
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, INSTM, UdR Parma Parco Area delle Scienze 17/A 43124 Parma Italy
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12
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Travis CR, Dumais RG, Treacy JW, Kean KM, Houk KN, Waters ML. Contribution of Electrostatic CH 3-π Interactions to Recognition of Histone Asymmetric Dimethylarginine by the SPIN1 Triple Tudor Domain. J Am Chem Soc 2024; 146:20678-20684. [PMID: 39023428 PMCID: PMC11407275 DOI: 10.1021/jacs.4c03463] [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] [Indexed: 07/20/2024]
Abstract
Methylation of arginine (Arg) residues on histones creates a new binding epitope, enabling recognition by aromatic cage binding pockets in Tudor domains; these protein-protein interactions (PPIs) govern gene expression. Despite their biological importance, the molecular details of methylated Arg recognition are poorly understood. While the desolvation, hydrogen bonding, and guanidinium stacking of methylated Arg have been explored in model systems and proposed to contribute to binding, direct interactions between the methyl groups and the aromatic residues in the binding pocket have not previously been investigated. Herein, we mechanistically study the CH3-π interactions between the SPIN1 triple Tudor domain and histone asymmetric dimethylarginine. We find that these CH3-π interactions are electrostatically tunable, exhibiting cation-π character, albeit attenuated relative to cation-π interactions with quaternary ammonium ions, offering key insight into how methylation of Arg alters its binding epitope to enable new PPIs.
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Affiliation(s)
- Christopher R Travis
- Department of Chemistry, CB 3290, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Ryan G Dumais
- Department of Chemistry, CB 3290, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Joseph W Treacy
- Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California 90095-1569, United States
| | - Kelsey M Kean
- Department of Chemistry, High Point University, High Point, North Carolina 27268, United States
| | - K N Houk
- Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California 90095-1569, United States
| | - Marcey L Waters
- Department of Chemistry, CB 3290, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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13
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Ren XG, Li W, Li WX, Yu WQ. Mechanism of Histone Arginine Methylation Dynamic Change in Cellular Stress. Int J Mol Sci 2024; 25:7562. [PMID: 39062806 PMCID: PMC11277302 DOI: 10.3390/ijms25147562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/03/2024] [Accepted: 06/29/2024] [Indexed: 07/28/2024] Open
Abstract
Histone arginine residue methylation is crucial for individual development and gene regulation. However, the dynamics of histone arginine methylation in response to cellular stress remains largely unexplored. In addition, the interplay and regulatory mechanisms between this and other histone modifications are important scientific questions that require further investigation. This study aimed to investigate the changes in histone arginine methylation in response to DNA damage. We report a global decrease in histone H3R26 symmetric dimethylation (H3R26me2s) and hypoacetylation at the H3K27 site in response to DNA damage. Notably, H3R26me2s exhibits a distribution pattern similar to that of H3K27ac across the genome, both of which are antagonistic to H3K27me3. Additionally, histone deacetylase 1 (HDAC1) may be recruited to the H3R26me2s demethylation region to mediate H3K27 deacetylation. These findings suggest crosstalk between H3R26me2s and H3K27ac in regulating gene expression.
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Affiliation(s)
| | | | | | - Wen-Qiang Yu
- Department of RNA Epigenetics, Faculty of Institute of Biomedical Sciences, Campus of Shanghai Medical College, Fudan University, Shanghai 200032, China; (X.-G.R.); (W.L.); (W.-X.L.)
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14
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Chen C, Ding Y, Huang Q, Zhang C, Zhao Z, Zhou H, Li D, Zhou G. Relationship between arginine methylation and vascular calcification. Cell Signal 2024; 119:111189. [PMID: 38670475 DOI: 10.1016/j.cellsig.2024.111189] [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: 01/30/2024] [Revised: 04/11/2024] [Accepted: 04/23/2024] [Indexed: 04/28/2024]
Abstract
In patients on maintenance hemodialysis (MHD), vascular calcification (VC) is an independent predictor of cardiovascular disease (CVD), which is the primary cause of death in chronic kidney disease (CKD). The main component of VC in CKD is the vascular smooth muscle cells (VSMCs). VC is an ordered, dynamic activity. Under the stresses of oxidative stress and calcium-‑phosphorus imbalance, VSMCs undergo osteogenic phenotypic transdifferentiation, which promotes the formation of VC. In addition to traditional epigenetics like RNA and DNA control, post-translational modifications have been discovered to be involved in the regulation of VC in recent years. It has been reported that the process of osteoblast differentiation is impacted by catalytic histone or non-histone arginine methylation. Its function in the osteogenic process is comparable to that of VC. Thus, we propose that arginine methylation regulates VC via many signaling pathways, including as NF-B, WNT, AKT/PI3K, TGF-/BMP/SMAD, and IL-6/STAT3. It might also regulate the VC-related calcification regulatory factors, oxidative stress, and endoplasmic reticulum stress. Consequently, we propose that arginine methylation regulates the calcification of the arteries and outline the regulatory mechanisms involved.
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Affiliation(s)
- Chen Chen
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Yuanyuan Ding
- Department of Pain Management, Shengjing Hospital, China Medical University, China
| | - Qun Huang
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Chen Zhang
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Zixia Zhao
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Hua Zhou
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Detian Li
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Guangyu Zhou
- Department of Nephrology, Shengjing Hospital, China Medical University, China.
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15
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Li X, Song Y, Mu W, Hou X, Ba T, Ji S. Dysregulation of arginine methylation in tumorigenesis. Front Mol Biosci 2024; 11:1420365. [PMID: 38911125 PMCID: PMC11190088 DOI: 10.3389/fmolb.2024.1420365] [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: 04/20/2024] [Accepted: 05/22/2024] [Indexed: 06/25/2024] Open
Abstract
Protein methylation, similar to DNA methylation, primarily involves post-translational modification (PTM) targeting residues of nitrogen-containing side-chains and other residues. Protein arginine methylation, occurred on arginine residue, is mainly mediated by protein arginine methyltransferases (PRMTs), which are ubiquitously present in a multitude of organisms and are intricately involved in the regulation of numerous biological processes. Specifically, PRMTs are pivotal in the process of gene transcription regulation, and protein function modulation. Abnormal arginine methylation, particularly in histones, can induce dysregulation of gene expression, thereby leading to the development of cancer. The recent advancements in modification mediated by PRMTs and cancer research have had a profound impact on our understanding of the abnormal modification involved in carcinogenesis and progression. This review will provide a defined overview of these recent progression, with the aim of augmenting our knowledge on the role of PRMTs in progression and their potential application in cancer therapy.
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Affiliation(s)
- Xiao Li
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Yaqiong Song
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Weiwei Mu
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Xiaoli Hou
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Te Ba
- Department of Shanxi University of Chinese Medicine, Jinzhong, Shanxi, China
| | - Shaoping Ji
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
- Department of Biochemistry and Molecular Biology, Medical School, Henan University, Kaifeng, Henan, China
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16
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Zhang S, Kiarasi F. Therapeutic effects of resveratrol on epigenetic mechanisms in age-related diseases: A comprehensive review. Phytother Res 2024; 38:2347-2360. [PMID: 38421057 DOI: 10.1002/ptr.8176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/28/2024] [Accepted: 02/10/2024] [Indexed: 03/02/2024]
Abstract
Recently, various studies have shown that epigenetic changes are associated with aging and age-related diseases. Both animal and human models have revealed that epigenetic processes are involved in aging mechanisms. These processes happen at multiple levels and include histone modification, DNA methylation, and changes in noncoding RNA expression. Consequently, changes in the organization of chromatin and DNA accessibility lead to the regulation of gene expression. With increasing awareness of the pivotal function of epigenetics in the aging process, researchers' attention has been drawn to how these epigenetic changes can be modified to prevent, stop, or reverse aging, senescence, and age-related diseases. Among various agents that can affect epigenetic, polyphenols are well-known phytochemicals found in fruits, vegetables, and plants. Polyphenols are found to modify epigenetic-related mechanisms in various diseases and conditions, such as metabolic disorders, obesity, neurodegenerative diseases, cancer, and cardiovascular diseases. Resveratrol (RSV) is a member of the stilbene subgroup of polyphenols which is derived from various plants, such as grapes, apples, and blueberries. Therefore, herein, we aim to summarize how RSV affects different epigenetic processes to change aging-related mechanisms. Furthermore, we discuss its roles in age-related diseases, such as Alzheimer's, Parkinson's, osteoporosis, and cardiovascular diseases.
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Affiliation(s)
| | - Farzam Kiarasi
- Department of Medical Nanotechnology, Applied Biophotonics Research Center, Science and Research Branch, Islamic Azad University, Tehran, Iran
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17
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Honda S, Hatamura M, Kunimoto Y, Ikeda S, Minami N. Chimeric PRMT6 protein produced by an endogenous retrovirus promoter regulates cell fate decision in mouse preimplantation embryos†. Biol Reprod 2024; 110:698-710. [PMID: 38196172 DOI: 10.1093/biolre/ioae002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 10/11/2023] [Accepted: 01/07/2023] [Indexed: 01/11/2024] Open
Abstract
Murine endogenous retrovirus with leucine tRNA primer, also known as MERVL, is expressed during zygotic genome activation in mammalian embryos. Here we show that protein arginine N-methyltransferase 6 (Prmt6) forms a chimeric transcript with MT2B2, one of the long terminal repeat sequences of murine endogenous retrovirus with leucine tRNA primer, and is translated into an elongated chimeric protein (PRMT6MT2B2) whose function differs from that of the canonical PRMT6 protein (PRMT6CAN) in mouse preimplantation embryos. Overexpression of PRMT6CAN in fibroblast cells increased asymmetric dimethylation of the third arginine residue of both histone H2A (H2AR3me2a) and histone H4 (H4R3me2a), while overexpression of PRMT6MT2B2 increased only H2AR3me2a. In addition, overexpression of PRMT6MT2B2 in one blastomere of mouse two-cell embryos promoted cell proliferation and differentiation of the blastomere into epiblast cells at the blastocyst stage, while overexpression of PRMT6CAN repressed cell proliferation. This is the first report of the translation of a chimeric protein (PRMT6MT2B2) in mouse preimplantation embryos. Our results suggest that analyzing chimeric transcripts with murine endogenous retrovirus with leucine tRNA primer will provide insight into the relationship between zygotic genome activation and subsequent intra- and extra-cellular lineage determination.
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Affiliation(s)
- Shinnosuke Honda
- Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Maho Hatamura
- Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Yuri Kunimoto
- Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Shuntaro Ikeda
- Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Naojiro Minami
- Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
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18
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Lossi L, Castagna C, Merighi A. An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions. Int J Mol Sci 2024; 25:3881. [PMID: 38612690 PMCID: PMC11011998 DOI: 10.3390/ijms25073881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
Epigenetic changes are changes in gene expression that do not involve alterations to the DNA sequence. These changes lead to establishing a so-called epigenetic code that dictates which and when genes are activated, thus orchestrating gene regulation and playing a central role in development, health, and disease. The brain, being mostly formed by cells that do not undergo a renewal process throughout life, is highly prone to the risk of alterations leading to neuronal death and neurodegenerative disorders, mainly at a late age. Here, we review the main epigenetic modifications that have been described in the brain, with particular attention on those related to the onset of developmental anomalies or neurodegenerative conditions and/or occurring in old age. DNA methylation and several types of histone modifications (acetylation, methylation, phosphorylation, ubiquitination, sumoylation, lactylation, and crotonylation) are major players in these processes. They are directly or indirectly involved in the onset of neurodegeneration in Alzheimer's or Parkinson's disease. Therefore, this review briefly describes the roles of these epigenetic changes in the mechanisms of brain development, maturation, and aging and some of the most important factors dynamically regulating or contributing to these changes, such as oxidative stress, inflammation, and mitochondrial dysfunction.
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Affiliation(s)
| | | | - Adalberto Merighi
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, 10095 Grugliasco, Italy; (L.L.); (C.C.)
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19
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Wei S, Zhang J, Zhao R, Shi R, An L, Yu Z, Zhang Q, Zhang J, Yao Y, Li H, Wang H. Histone lactylation promotes malignant progression by facilitating USP39 expression to target PI3K/AKT/HIF-1α signal pathway in endometrial carcinoma. Cell Death Discov 2024; 10:121. [PMID: 38459014 PMCID: PMC10923933 DOI: 10.1038/s41420-024-01898-4] [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: 11/24/2023] [Revised: 02/23/2024] [Accepted: 02/28/2024] [Indexed: 03/10/2024] Open
Abstract
Histone lactylation has been reported to involve in tumorigenesis and development. However, its biological regulatory mechanism in endometrial carcinoma (EC) is yet to be reported in detail. In the present study, we evaluated the modification levels of global lactylation in EC tissues by immunohistochemistry and western blot, and it was elevated. The non-metabolizable glucose analog 2-deoxy-d-glucose (2-DG) and oxamate treatment could decrease the level of lactylation so as to inhibit the proliferation and migration ability, induce apoptosis significantly, and arrest the cell cycle of EC cells. Mechanically, histone lactylation stimulated USP39 expression to promote tumor progression. Moreover, USP39 activated PI3K/AKT/HIF-1α signaling pathway via interacting with and stabilizing PGK1 to stimulate glycolysis. The results of present study suggest that histone lactylation plays an important role in the progression of EC by promoting the malignant biological behavior of EC cells, thus providing insights into potential therapeutic strategies for endometrial cancer.
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Affiliation(s)
- Sitian Wei
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Jun Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Rong Zhao
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Rui Shi
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Lanfen An
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Zhicheng Yu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Qi Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Jiarui Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Yuwei Yao
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Haojia Li
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Hongbo Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
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20
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Lu L, Ye Z, Zhang R, Olsen JV, Yuan Y, Mao Y. ETD-Based Proteomic Profiling Improves Arginine Methylation Identification and Reveals Novel PRMT5 Substrates. J Proteome Res 2024; 23:1014-1027. [PMID: 38272855 DOI: 10.1021/acs.jproteome.3c00724] [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: 01/27/2024]
Abstract
Protein arginine methylations are important post-translational modifications (PTMs) in eukaryotes, regulating many biological processes. However, traditional collision-based mass spectrometry methods inevitably cause neutral losses of methylarginines, preventing the deep mining of biologically important sites. Herein we developed an optimized mass spectrometry workflow based on electron-transfer dissociation (ETD) with supplemental activation for proteomic profiling of arginine methylation in human cells. Using symmetric dimethylarginine (sDMA) as an example, we show that the ETD-based optimized workflow significantly improved the identification and site localization of sDMA. Quantitative proteomics identified 138 novel sDMA sites as potential PRMT5 substrates in HeLa cells. Further biochemical studies on SERBP1, a newly identified PRMT5 substrate, confirmed the coexistence of sDMA and asymmetric dimethylarginine in the central RGG/RG motif, and loss of either methylation caused increased the recruitment of SERBP1 to stress granules under oxidative stress. Overall, our optimized workflow not only enabled the identification and localization of extensive, nonoverlapping sDMA sites in human cells but also revealed novel PRMT5 substrates whose sDMA may play potentially important biological functions.
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Affiliation(s)
- Lingzi Lu
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Zilu Ye
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Rou Zhang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Jesper V Olsen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Yanqiu Yuan
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
| | - Yang Mao
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Sun Yat-sen University, Guangzhou 510006, China
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21
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Jbeli AH, Yang L, Xia H, Gilbertsen AJ, Bitterman PB, Henke CA. Brg1/PRMT5 nuclear complex epigenetically regulates FOXO1 in IPF mesenchymal progenitor cells. Am J Physiol Lung Cell Mol Physiol 2024; 326:L344-L352. [PMID: 38252663 PMCID: PMC11281790 DOI: 10.1152/ajplung.00248.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 12/15/2023] [Accepted: 01/15/2024] [Indexed: 01/24/2024] Open
Abstract
We have discovered intrinsically fibrogenic mesenchymal progenitor cells (MPCs) in the human idiopathic pulmonary fibrosis (IPF) lung. IPF MPCs display a durably distinct transcriptome, suggesting that they have undergone epigenetic modifications. Prior studies indicate that the chromatin remodeler Brg1 associates with the arginine methyltransferase PRMT5 to epigenetically regulate transcription factors. We hypothesize that a Brg1/PRMT5 nuclear complex epigenetically regulates critical nodes in IPF MPC self-renewal signaling networks. IPF and control MPCs were isolated from primary mesenchymal cell lines established from IPF and control patients. RNA-sequencing identified increased expression of the FOXO1 transcription factor in IPF MPCs compared with controls, a result we confirmed by Q-PCR and Western blot analysis. Immunoprecipitation identified a CD44/Brg1/PRMT5 nuclear complex in IPF MPCs. Chromatin immunoprecipitation assays showed that PRMT5 and its methylation mark H3R2me2 are enriched on the FOXO1 promoter. We show that loss of Brg1 and PRMT5 function decreases FOXO1 expression and impairs IPF MPC self-renewal, and that loss of FOXO1 function decreases IPF MPC self-renewal and expression of the SOX2 and OCT4 stemness markers. Our findings indicate that the FOXO1 gene is overexpressed in IPF MPCs in a CD44/Brg1/PRMT5 nuclear complex-dependent manner. Our data suggest that Brg1 alters chromatin accessibility, enriching PRMT5 occupancy on the FOXO1 promoter, and PRMT5 methylates histone H3 arginine 2 (H3R2) on the FOXO1 promoter, increasing its expression. Our data are in accord with the concept that this coordinated interplay is responsible for promoting IPF MPC self-renewal and maintaining a critical pool of fibrogenic MPCs that drive IPF progression.NEW & NOTEWORTHY Our research offers valuable understanding regarding the epigenetic control of IPF MPC. The data we obtained strongly support the idea that the coordination between chromatin remodeling and histone methylation plays a key role in regulating transcription factors. Specifically, our findings indicate that FOXO1, an essential transcription factor, likely governs the self-renewal of IPF MPC, which is crucial for maintaining a critical pool of fibrogenic MPCs. This interplay could be an important therapeutic target.
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Affiliation(s)
- Aiham H Jbeli
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
| | - Libang Yang
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
| | - Hong Xia
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
| | - Adam J Gilbertsen
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
| | - Peter B Bitterman
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
| | - Craig A Henke
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
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22
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Taniguchi R, Moriya Y, Dohmae N, Suzuki T, Nakahara K, Kubota S, Takasugi N, Uehara T. Attenuation of protein arginine dimethylation via S-nitrosylation of protein arginine methyltransferase 1. J Pharmacol Sci 2024; 154:209-217. [PMID: 38395522 DOI: 10.1016/j.jphs.2023.12.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/14/2023] [Accepted: 12/27/2023] [Indexed: 02/25/2024] Open
Abstract
Upregulation of nitric oxide (NO) production contributes to the pathogenesis of numerous diseases via S-nitrosylation, a post-translational modification of proteins. This process occurs due to the oxidative reaction between NO and a cysteine thiol group; however, the extent of this reaction remains unknown. S-Nitrosylation of PRMT1, a major asymmetric arginine methyltransferase of histones and numerous RNA metabolic proteins, was induced by NO donor treatment. We found that nitrosative stress leads to S-nitrosylation of cysteine 119, located near the active site, and attenuates the enzymatic activity of PRMT1. Interestingly, RNA sequencing analysis revealed similarities in the changes in expression elicited by NO and PRMT1 inhibitors or knockdown. A comprehensive search for PRMT1 substrates using the proximity-dependent biotin identification method highlighted many known and new substrates, including RNA-metabolizing enzymes. To validate this result, we selected the RNA helicase DDX3 and demonstrated that arginine methylation of DDX3 is induced by PRMT1 and attenuated by NO treatment. Our results suggest the existence of a novel regulatory system associated with transcription and RNA metabolism via protein S-nitrosylation.
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Affiliation(s)
- Rikako Taniguchi
- Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yuto Moriya
- Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Naoshi Dohmae
- Biomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan
| | - Takehiro Suzuki
- Biomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan
| | - Kengo Nakahara
- Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Sho Kubota
- Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Nobumasa Takasugi
- Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Takashi Uehara
- Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
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23
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Lumpp T, Stößer S, Fischer F, Hartwig A, Köberle B. Role of Epigenetics for the Efficacy of Cisplatin. Int J Mol Sci 2024; 25:1130. [PMID: 38256203 PMCID: PMC10816946 DOI: 10.3390/ijms25021130] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/05/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
The clinical utility of the chemotherapeutic agent cisplatin is restricted by cancer drug resistance, which is either intrinsic to the tumor or acquired during therapy. Epigenetics is increasingly recognized as a factor contributing to cisplatin resistance and hence influences drug efficacy and clinical outcomes. In particular, epigenetics regulates gene expression without changing the DNA sequence. Common types of epigenetic modifications linked to chemoresistance are DNA methylation, histone modification, and non-coding RNAs. This review provides an overview of the current findings of various epigenetic modifications related to cisplatin efficacy in cell lines in vitro and in clinical tumor samples. Furthermore, it discusses whether epigenetic alterations might be used as predictors of the platinum agent response in order to prevent avoidable side effects in patients with resistant malignancies. In addition, epigenetic targeting therapies are described as a possible strategy to render cancer cells more susceptible to platinum drugs.
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Affiliation(s)
| | | | | | | | - Beate Köberle
- Department Food Chemistry and Toxicology, Institute of Applied Biosciences, Karlsruhe Institute of Technology, Adenauerring 20a, 76131 Karlsruhe, Germany; (T.L.); (S.S.); (F.F.); (A.H.)
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24
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Song C, Kim MY, Cho JY. The Role of Protein Methyltransferases in Immunity. Molecules 2024; 29:360. [PMID: 38257273 PMCID: PMC10819338 DOI: 10.3390/molecules29020360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
The immune system protects our body from bacteria, viruses, and toxins and removes malignant cells. Activation of immune cells requires the onset of a network of important signaling proteins. Methylation of these proteins affects their structure and biological function. Under stimulation, T cells, B cells, and other immune cells undergo activation, development, proliferation, differentiation, and manufacture of cytokines and antibodies. Methyltransferases alter the above processes and lead to diverse outcomes depending on the degree and type of methylation. In the previous two decades, methyltransferases have been reported to mediate a great variety of immune stages. Elucidating the roles of methylation in immunity not only contributes to understanding the immune mechanism but is helpful in the development of new immunotherapeutic strategies. Hence, we review herein the studies on methylation in immunity, aiming to provide ideas for new approaches.
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Affiliation(s)
- Chaoran Song
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea;
| | - Mi-Yeon Kim
- School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea
| | - Jae Youl Cho
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea;
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25
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Holtz AG, Lowe TL, Aoki Y, Kubota Y, Hoffman RM, Clarke SG. Asymmetric and symmetric protein arginine methylation in methionine-addicted human cancer cells. PLoS One 2023; 18:e0296291. [PMID: 38134182 PMCID: PMC10745221 DOI: 10.1371/journal.pone.0296291] [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: 08/22/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023] Open
Abstract
The methionine addiction of cancer cells is known as the Hoffman effect. While non-cancer cells in culture can utilize homocysteine in place of methionine for cellular growth, most cancer cells require exogenous methionine for proliferation. It has been suggested that a biochemical basis of this effect is the increased utilization of methionine for S-adenosylmethionine, the major methyl donor for a variety of cellular methyltransferases. Recent studies have pointed to the role of S-adenosylmethionine-dependent protein arginine methyltransferases (PRMTs) in cell proliferation and cancer. To further understand the biochemical basis of the methionine addiction of cancer cells, we compared protein arginine methylation in two previously described isogenic cell lines, a methionine-addicted 143B human osteosarcoma cell line and its less methionine-dependent revertant. Previous work showed that the revertant cells were significantly less malignant than the parental cells. In the present study, we utilized antibodies to detect the asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) products of PRMTs in polypeptides from cellular extracts and purified histone preparations of these cell lines fractionated by SDS-PAGE. Importantly, we observed little to no differences in the banding patterns of ADMA- and SDMA-containing species between the osteosarcoma parental and revertant cell lines. Furthermore, enzymatic activity assays using S-adenosyl-ʟ-[methyl-3H] methionine, recombinantly purified PRMT enzymes, cell lysates, and specific PRMT inhibitors revealed no major differences in radiolabeled polypeptides on SDS-PAGE gels. Taken together, these results suggest that changes in protein arginine methylation may not be major contributors to the Hoffman effect and that other consequences of methionine addiction may be more important in the metastasis and malignancy of osteosarcoma and potentially other cancers.
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Affiliation(s)
- Ashley G Holtz
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, United States of America
| | - Troy L Lowe
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, United States of America
| | - Yusuke Aoki
- AntiCancer, Inc, San Diego, CA, United States of America
- Department of Surgery, University of California, San Diego, La Jolla, CA, United States of America
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Yutaro Kubota
- AntiCancer, Inc, San Diego, CA, United States of America
- Department of Surgery, University of California, San Diego, La Jolla, CA, United States of America
| | - Robert M Hoffman
- AntiCancer, Inc, San Diego, CA, United States of America
- Department of Surgery, University of California, San Diego, La Jolla, CA, United States of America
| | - Steven G Clarke
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, United States of America
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26
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Li Y, Dobrolecki LE, Sallas C, Zhang X, Kerr TD, Bisht D, Wang Y, Awasthi S, Kaundal B, Wu S, Peng W, Mendillo ML, Lu Y, Jeter CR, Peng G, Liu J, Westin SN, Sood AK, Lewis MT, Das J, Yi SS, Bedford MT, McGrail DJ, Sahni N. PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition. Cell Rep Med 2023; 4:101326. [PMID: 38118413 PMCID: PMC10772459 DOI: 10.1016/j.xcrm.2023.101326] [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: 04/16/2023] [Revised: 09/07/2023] [Accepted: 11/17/2023] [Indexed: 12/22/2023]
Abstract
Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.
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Affiliation(s)
- Yang Li
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lacey E Dobrolecki
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
| | - Christina Sallas
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
| | - Xudong Zhang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Travis D Kerr
- Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA
| | - Deepa Bisht
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yalong Wang
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sharad Awasthi
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Babita Kaundal
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Siqi Wu
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Weiyi Peng
- Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - Marc L Mendillo
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Yiling Lu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Collene R Jeter
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Guang Peng
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jinsong Liu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shannon N Westin
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael T Lewis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
| | - Jishnu Das
- Center for Systems Immunology, Department of Immunology, and Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - S Stephen Yi
- Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA; Interdisciplinary Life Sciences Graduate Programs (ILSGP), College of Natural Sciences, The University of Texas at Austin, Austin, TX, USA; Oden Institute for Computational Engineering and Sciences (ICES), The University of Texas at Austin, Austin, TX, USA; Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX, USA
| | - Mark T Bedford
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Daniel J McGrail
- Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA; Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
| | - Nidhi Sahni
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Quantitative and Computational Biosciences Program, Baylor College of Medicine, Houston, TX, USA.
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27
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Nie H, Li Q, Pan W. The emerging roles of protein arginine methyltransferases in antiviral innate immune signaling pathways. Front Microbiol 2023; 14:1322929. [PMID: 38116532 PMCID: PMC10728285 DOI: 10.3389/fmicb.2023.1322929] [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: 10/17/2023] [Accepted: 11/21/2023] [Indexed: 12/21/2023] Open
Abstract
The Protein Arginine Methyltransferases (PRMTs) family is involved in various biological processes, including gene transcription, pre-mRNA splicing, mRNA translation, and protein stability. Recently, mounting evidence has shown that PRMTs also play critical roles in regulating the host antiviral immune response, either in an enzymatic activity dependent or independent manner. This review aims to provide an overview of the recent findings regarding the function and regulatory mechanisms of PRMTs in the antiviral response. These findings have the potential to aid in the discovery and design of novel therapeutic strategies for viral infections.
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Affiliation(s)
| | | | - Wei Pan
- Key Laboratory of Animal Resistance Biology of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan, China
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28
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Musawi S, Donnio LM, Zhao Z, Magnani C, Rassinoux P, Binda O, Huang J, Jacquier A, Coudert L, Lomonte P, Martinat C, Schaeffer L, Mottet D, Côté J, Mari PO, Giglia-Mari G. Nucleolar reorganization after cellular stress is orchestrated by SMN shuttling between nuclear compartments. Nat Commun 2023; 14:7384. [PMID: 37968267 PMCID: PMC10652021 DOI: 10.1038/s41467-023-42390-4] [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: 10/13/2022] [Accepted: 10/10/2023] [Indexed: 11/17/2023] Open
Abstract
Spinal muscular atrophy is an autosomal recessive neuromuscular disease caused by mutations in the multifunctional protein Survival of Motor Neuron, or SMN. Within the nucleus, SMN localizes to Cajal bodies, which are associated with nucleoli, nuclear organelles dedicated to the first steps of ribosome biogenesis. The highly organized structure of the nucleolus can be dynamically altered by genotoxic agents. RNAP1, Fibrillarin, and nucleolar DNA are exported to the periphery of the nucleolus after genotoxic stress and, once DNA repair is fully completed, the organization of the nucleolus is restored. We find that SMN is required for the restoration of the nucleolar structure after genotoxic stress. During DNA repair, SMN shuttles from the Cajal bodies to the nucleolus. This shuttling is important for nucleolar homeostasis and relies on the presence of Coilin and the activity of PRMT1.
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Affiliation(s)
- Shaqraa Musawi
- Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, 68008, Lyon, France
- Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Lise-Marie Donnio
- Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, 68008, Lyon, France.
| | - Zehui Zhao
- Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, 68008, Lyon, France
| | - Charlène Magnani
- Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, 68008, Lyon, France
| | - Phoebe Rassinoux
- Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, 68008, Lyon, France
| | - Olivier Binda
- Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, 68008, Lyon, France
- Faculty of Medicine, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, K1H 8M5, Ontario, Canada
| | - Jianbo Huang
- Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, 68008, Lyon, France
| | - Arnaud Jacquier
- Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, 68008, Lyon, France
| | - Laurent Coudert
- Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, 68008, Lyon, France
| | - Patrick Lomonte
- Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, 68008, Lyon, France
| | - Cécile Martinat
- INSERM/UEPS UMR 861, Paris Saclay Université, I-STEM, 91100, Corbeil-Essonnes, France
| | - Laurent Schaeffer
- Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, 68008, Lyon, France
| | - Denis Mottet
- GIGA-Molecular Biology of Diseases, Gene Expression and Cancer Laboratory, B34 + 1, University of Liege, Avenue de l'Hôpital 1, B-4000, Liège, Belgium
| | - Jocelyn Côté
- Faculty of Medicine, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, K1H 8M5, Ontario, Canada
| | - Pierre-Olivier Mari
- Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, 68008, Lyon, France
| | - Giuseppina Giglia-Mari
- Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, 68008, Lyon, France.
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29
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Zhang C, He Y, Sun X, Wei W, Liu Y, Rao Y. PROTACs Targeting Epigenetic Proteins. ACTA MATERIA MEDICA 2023; 2:409-429. [PMID: 39221114 PMCID: PMC11364368 DOI: 10.15212/amm-2023-0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Epigenetics, a field that investigates alterations in gene function that can be inherited without changes in DNA sequence, encompasses molecular pathways such as histone variants, posttranslational modifications of amino acids, and covalent modifications of DNA bases. These pathways modulate the transformation of genotypes into specific phenotypes. Epigenetics plays a substantial role in cell growth, development, and differentiation by dynamically regulating gene transcription and ensuring genomic stability. This regulation is carried out by three key players: writers, readers, and erasers. In recent years, epigenetic proteins have played a crucial role in epigenetic regulation and have gradually become important targets in drug research and development. Targeted therapy is an essential strategy; however, the effectiveness of targeted drugs is often limited by drug resistance, posing a significant dilemma in clinical practice. Targeted protein degradation technologies, including proteolysis-targeting chimeras (PROTACs), have great potential in overcoming drug resistance and targeting undruggable targets. These areas of research are gaining increasing attention to various epigenetic related disease. In this review, we have provided a summary of the recently developed degraders targeting epigenetic readers, writers, and erasers. Additionally, we have outlined new applications for epigenetic protein degraders. Finally, we have addressed several unresolved challenges within the PROTAC field and offered potential solutions from our perspective. As the field continues to advance, the integration of these innovative methodologies holds great promise for addressing the challenges associated with PROTAC development.
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Affiliation(s)
- Chao Zhang
- Changping Laboratory, Beijing 102206, China
| | - Yuna He
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
| | - Xiuyun Sun
- Changping Laboratory, Beijing 102206, China
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, United States
| | - Yanlong Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Yu Rao
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
- Changping Laboratory, Beijing 102206, China
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30
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Cao MT, Feng Y, Zheng YG. Protein arginine methyltransferase 6 is a novel substrate of protein arginine methyltransferase 1. World J Biol Chem 2023; 14:84-98. [PMID: 37901302 PMCID: PMC10600687 DOI: 10.4331/wjbc.v14.i5.84] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/08/2023] [Accepted: 09/26/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND Post-translational modifications play key roles in various biological processes. Protein arginine methyltransferases (PRMTs) transfer the methyl group to specific arginine residues. Both PRMT1 and PRMT6 have emerges as crucial factors in the development and progression of multiple cancer types. We posit that PRMT1 and PRMT6 might interplay directly or in-directly in multiple ways accounting for shared disease phenotypes. AIM To investigate the mechanism of the interaction between PRMT1 and PRMT6. METHODS Gel electrophoresis autoradiography was performed to test the methyltranferase activity of PRMTs and characterize the kinetics parameters of PRMTs. Liquid chromatography-tandem mass spectrometryanalysis was performed to detect the PRMT6 methylation sites. RESULTS In this study we investigated the interaction between PRMT1 and PRMT6, and PRMT6 was shown to be a novel substrate of PRMT1. We identified specific arginine residues of PRMT6 that are methylated by PRMT1, with R106 being the major methylation site. Combined biochemical and cellular data showed that PRMT1 downregulates the enzymatic activity of PRMT6 in histone H3 methylation. CONCLUSION PRMT6 is methylated by PRMT1 and R106 is a major methylation site induced by PRMT1. PRMT1 methylation suppresses the activity of PRMT6.
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Affiliation(s)
- Meng-Tong Cao
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, United States
| | - You Feng
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, United States
| | - Y George Zheng
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, United States
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Zhu N, Guo ZF, Kazama K, Yi B, Tongmuang N, Yao H, Yang R, Zhang C, Qin Y, Han L, Sun J. Epigenetic regulation of vascular smooth muscle cell phenotypic switch and neointimal formation by PRMT5. Cardiovasc Res 2023; 119:2244-2255. [PMID: 37486354 PMCID: PMC10578915 DOI: 10.1093/cvr/cvad110] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 03/20/2023] [Accepted: 04/08/2023] [Indexed: 07/25/2023] Open
Abstract
AIMS Phenotypic transition of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic state is involved in the development of cardiovascular diseases, including atherosclerosis, hypertension, and post-angioplasty restenosis. Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) has been implicated in multiple cellular processes, however, its role in VSMC biology remains undetermined. The objective of this study was to determine the role of PRMTs in VSMC phenotypic switch and vascular remodelling after injury. METHODS AND RESULTS Our results show that PRMT5 is the most abundantly expressed PRMT in human aortic SMCs, and its expression is up-regulated in platelet-derived growth factor (PDGF)-stimulated VSMCs, human atherosclerotic lesions, and rat carotid arteries after injury, as determined by western blot and immunohistochemical staining. PRMT5 overexpression inhibits the expression of SMC marker genes and promotes VSMC proliferation and migration, while silencing PRMT5 exerts the opposite effects. Mechanistically, we found that PRMT5 overexpression led to histone di-methylation of H3R8 and H4R3, which in turn attenuates acetylation of H3K9 and H4, thus limiting recruitment of the SRF/myocardin complexes to the CArG boxes of SMC marker genes. Furthermore, both SMC-specific deletion of PRMT5 in mice and local delivery of lentivirus expressing shPRMT5 to rat carotid arteries significantly attenuated neointimal formation after injury. Likewise, pharmacological inhibition of PRMT5 by EPZ015666 markedly inhibited carotid artery ligation-induced neointimal formation in mice. CONCLUSIONS Our results identify PRMT5 as a novel regulator in VSMC phenotypic switch and suggest that inhibition of PRMT5 may represent an effective therapeutic strategy for proliferative vascular diseases.
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Affiliation(s)
- Ni Zhu
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA
| | - Zhi-Fu Guo
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA
| | - Kyosuke Kazama
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA
| | - Bing Yi
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA
| | - Nopprarat Tongmuang
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA
| | - Huijuan Yao
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA
| | - Ruifeng Yang
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA
| | - Chen Zhang
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA
| | - Yongwen Qin
- Department of Cardiovascular Medicine, Changhai Hospital, Naval Medical University, 168 Changhai Rd, Shanghai 200433, China
| | - Lin Han
- Department of Cardiovascular Medicine, Changhai Hospital, Naval Medical University, 168 Changhai Rd, Shanghai 200433, China
| | - Jianxin Sun
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA
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32
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Shi M, Wang C, Wang P, Yun F, Liu Z, Ye F, Wei L, Liao W. Role of methylation in vernalization and photoperiod pathway: a potential flowering regulator? HORTICULTURE RESEARCH 2023; 10:uhad174. [PMID: 37841501 PMCID: PMC10569243 DOI: 10.1093/hr/uhad174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 08/23/2023] [Indexed: 10/17/2023]
Abstract
Recognized as a pivotal developmental transition, flowering marks the continuation of a plant's life cycle. Vernalization and photoperiod are two major flowering pathways orchestrating numerous florigenic signals. Methylation, including histone, DNA and RNA methylation, is one of the recent foci in plant development. Considerable studies reveal that methylation seems to show an increasing potential regulatory role in plant flowering via altering relevant gene expression without altering the genetic basis. However, little has been reviewed about whether and how methylation acts on vernalization- and photoperiod-induced flowering before and after FLOWERING LOCUS C (FLC) reactivation, what role RNA methylation plays in vernalization- and photoperiod-induced flowering, how methylation participates simultaneously in both vernalization- and photoperiod-induced flowering, the heritability of methylation memory under the vernalization/photoperiod pathway, and whether and how methylation replaces vernalization/photoinduction to regulate flowering. Our review provides insight about the crosstalk among the genetic control of the flowering gene network, methylation (methyltransferases/demethylases) and external signals (cold, light, sRNA and phytohormones) in vernalization and photoperiod pathways. The existing evidence that RNA methylation may play a potential regulatory role in vernalization- and photoperiod-induced flowering has been gathered and represented for the first time. This review speculates about and discusses the possibility of substituting methylation for vernalization and photoinduction to promote flowering. Current evidence is utilized to discuss the possibility of future methylation reagents becoming flowering regulators at the molecular level.
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Affiliation(s)
- Meimei Shi
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China
| | - Chunlei Wang
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China
| | - Peng Wang
- Vegetable and Flower Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Fahong Yun
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China
| | - Zhiya Liu
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China
| | - Fujin Ye
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China
| | - Lijuan Wei
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China
| | - Weibiao Liao
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China
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Bray C, Balcells C, McNeish IA, Keun HC. The potential and challenges of targeting MTAP-negative cancers beyond synthetic lethality. Front Oncol 2023; 13:1264785. [PMID: 37795443 PMCID: PMC10546069 DOI: 10.3389/fonc.2023.1264785] [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: 07/21/2023] [Accepted: 09/04/2023] [Indexed: 10/06/2023] Open
Abstract
Approximately 15% of cancers exhibit loss of the chromosomal locus 9p21.3 - the genomic location of the tumour suppressor gene CDKN2A and the methionine salvage gene methylthioadenosine phosphorylase (MTAP). A loss of MTAP increases the pool of its substrate methylthioadenosine (MTA), which binds to and inhibits activity of protein arginine methyltransferase 5 (PRMT5). PRMT5 utilises the universal methyl donor S-adenosylmethionine (SAM) to methylate arginine residues of protein substrates and regulate their activity, notably histones to regulate transcription. Recently, targeting PRMT5, or MAT2A that impacts PRMT5 activity by producing SAM, has shown promise as a therapeutic strategy in oncology, generating synthetic lethality in MTAP-negative cancers. However, clinical development of PRMT5 and MAT2A inhibitors has been challenging and highlights the need for further understanding of the downstream mediators of drug effects. Here, we discuss the rationale and methods for targeting the MAT2A/PRMT5 axis for cancer therapy. We evaluate the current limitations in our understanding of the mechanism of MAT2A/PRMT5 inhibitors and identify the challenges that must be addressed to maximise the potential of these drugs. In addition, we review the current literature defining downstream effectors of PRMT5 activity that could determine sensitivity to MAT2A/PRMT5 inhibition and therefore present a rationale for novel combination therapies that may not rely on synthetic lethality with MTAP loss.
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Affiliation(s)
- Chandler Bray
- Cancer Metabolism & Systems Toxicology Group, Division of Cancer, Department of Surgery & Cancer, Imperial College London, London, United Kingdom
| | - Cristina Balcells
- Cancer Metabolism & Systems Toxicology Group, Division of Cancer, Department of Surgery & Cancer, Imperial College London, London, United Kingdom
| | - Iain A. McNeish
- Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Hector C. Keun
- Cancer Metabolism & Systems Toxicology Group, Division of Cancer, Department of Surgery & Cancer, Imperial College London, London, United Kingdom
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34
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Brown T, Nguyen T, Zhou B, Zheng YG. Chemical probes and methods for the study of protein arginine methylation. RSC Chem Biol 2023; 4:647-669. [PMID: 37654509 PMCID: PMC10467615 DOI: 10.1039/d3cb00018d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 07/28/2023] [Indexed: 09/02/2023] Open
Abstract
Protein arginine methylation is a widespread post-translational modification (PTM) in eukaryotic cells. This chemical modification in proteins functionally modulates diverse cellular processes from signal transduction, gene expression, and DNA damage repair to RNA splicing. The chemistry of arginine methylation entails the transfer of the methyl group from S-adenosyl-l-methionine (AdoMet, SAM) onto a guanidino nitrogen atom of an arginine residue of a target protein. This reaction is catalyzed by about 10 members of protein arginine methyltransferases (PRMTs). With impacts on a variety of cellular processes, aberrant expression and activity of PRMTs have been shown in many disease conditions. Particularly in oncology, PRMTs are commonly overexpressed in many cancerous tissues and positively correlated with tumor initiation, development and progression. As such, targeting PRMTs is increasingly recognized as an appealing therapeutic strategy for new drug discovery. In the past decade, a great deal of research efforts has been invested in illuminating PRMT functions in diseases and developing chemical probes for the mechanistic study of PRMTs in biological systems. In this review, we provide a brief developmental history of arginine methylation along with some key updates in arginine methylation research, with a particular emphasis on the chemical aspects of arginine methylation. We highlight the research endeavors for the development and application of chemical approaches and chemical tools for the study of functions of PRMTs and arginine methylation in regulating biology and disease.
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Affiliation(s)
- Tyler Brown
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia Athens GA 30602 USA +1-(706) 542-5358 +1-(706) 542-0277
| | - Terry Nguyen
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia Athens GA 30602 USA +1-(706) 542-5358 +1-(706) 542-0277
| | - Bo Zhou
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia Athens GA 30602 USA +1-(706) 542-5358 +1-(706) 542-0277
| | - Y George Zheng
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia Athens GA 30602 USA +1-(706) 542-5358 +1-(706) 542-0277
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Kim KH, Jia Z, Snyder M, Chen J, Qiu J, Oprescu SN, Chen X, Syed SA, Yue F, Roseguini BT, Imbalzano AN, Hu C, Kuang S. PRMT5 links lipid metabolism to contractile function of skeletal muscles. EMBO Rep 2023; 24:e57306. [PMID: 37334900 PMCID: PMC10398672 DOI: 10.15252/embr.202357306] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/30/2023] [Accepted: 06/05/2023] [Indexed: 06/21/2023] Open
Abstract
Skeletal muscle plays a key role in systemic energy homeostasis besides its contractile function, but what links these functions is poorly defined. Protein Arginine Methyl Transferase 5 (PRMT5) is a well-known oncoprotein but also expressed in healthy tissues with unclear physiological functions. As adult muscles express high levels of Prmt5, we generated skeletal muscle-specific Prmt5 knockout (Prmt5MKO ) mice. We observe reduced muscle mass, oxidative capacity, force production, and exercise performance in Prmt5MKO mice. The motor deficiency is associated with scarce lipid droplets in myofibers due to defects in lipid biosynthesis and accelerated degradation. Specifically, PRMT5 deletion reduces dimethylation and stability of Sterol Regulatory Element-Binding Transcription Factor 1a (SREBP1a), a master regulator of de novo lipogenesis. Moreover, Prmt5MKO impairs the repressive H4R3 symmetric dimethylation at the Pnpla2 promoter, elevating the level of its encoded protein ATGL, the rate-limiting enzyme catalyzing lipolysis. Accordingly, skeletal muscle-specific double knockout of Pnpla2 and Prmt5 normalizes muscle mass and function. Together, our findings delineate a physiological function of PRMT5 in linking lipid metabolism to contractile function of myofibers.
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Affiliation(s)
- Kun Ho Kim
- Department of Animal SciencesPurdue UniversityWest LafayetteINUSA
| | - Zhihao Jia
- Department of Animal SciencesPurdue UniversityWest LafayetteINUSA
| | - Madigan Snyder
- Department of Animal SciencesPurdue UniversityWest LafayetteINUSA
- Department of Biological SciencesPurdue UniversityWest LafayetteINUSA
| | - Jingjuan Chen
- Department of Animal SciencesPurdue UniversityWest LafayetteINUSA
| | - Jiamin Qiu
- Department of Animal SciencesPurdue UniversityWest LafayetteINUSA
| | - Stephanie N Oprescu
- Department of Animal SciencesPurdue UniversityWest LafayetteINUSA
- Department of Biological SciencesPurdue UniversityWest LafayetteINUSA
| | - Xiyue Chen
- Department of Animal SciencesPurdue UniversityWest LafayetteINUSA
| | - Sabriya A Syed
- Department of Biochemistry and Molecular PharmacologyUniversity of Massachusetts Medical SchoolWorcesterMAUSA
| | - Feng Yue
- Department of Animal SciencesPurdue UniversityWest LafayetteINUSA
| | - Bruno T Roseguini
- Department of Health and KinesiologyPurdue UniversityWest LafayetteINUSA
| | - Anthony N Imbalzano
- Department of Biochemistry and Molecular PharmacologyUniversity of Massachusetts Medical SchoolWorcesterMAUSA
| | - Changdeng Hu
- Department of Medicinal Chemistry and Molecular PharmacologyPurdue UniversityWest LafayetteINUSA
- Center for Cancer ResearchPurdue UniversityWest LafayetteINUSA
| | - Shihuan Kuang
- Department of Animal SciencesPurdue UniversityWest LafayetteINUSA
- Center for Cancer ResearchPurdue UniversityWest LafayetteINUSA
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36
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Lucky AB, Wang C, Liu M, Liang X, Min H, Fan Q, Siddiqui FA, Adapa SR, Li X, Jiang RHY, Chen X, Cui L, Miao J. A type II protein arginine methyltransferase regulates merozoite invasion in Plasmodium falciparum. Commun Biol 2023; 6:659. [PMID: 37349497 PMCID: PMC10287762 DOI: 10.1038/s42003-023-05038-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 06/12/2023] [Indexed: 06/24/2023] Open
Abstract
Protein arginine methyltransferases (PRMTs) regulate many important cellular processes, such as transcription and RNA processing in model organisms but their functions in human malaria parasites are not elucidated. Here, we characterize PfPRMT5 in Plasmodium falciparum, which catalyzes symmetric dimethylation of histone H3 at R2 (H3R2me2s) and R8, and histone H4 at R3 in vitro. PfPRMT5 disruption results in asexual stage growth defects primarily due to lower invasion efficiency of the merozoites. Transcriptomic analysis reveals down-regulation of many transcripts related to invasion upon PfPRMT5 disruption, in agreement with H3R2me2s being an active chromatin mark. Genome-wide chromatin profiling detects extensive H3R2me2s marking of genes of different cellular processes, including invasion-related genes in wildtype parasites and PfPRMT5 disruption leads to the depletion of H3R2me2s. Interactome studies identify the association of PfPRMT5 with invasion-related transcriptional regulators such as AP2-I, BDP1, and GCN5. Furthermore, PfPRMT5 is associated with the RNA splicing machinery, and PfPRMT5 disruption caused substantial anomalies in RNA splicing events, including those for invasion-related genes. In summary, PfPRMT5 is critical for regulating parasite invasion and RNA splicing in this early-branching eukaryote.
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Affiliation(s)
- Amuza Byaruhanga Lucky
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA
| | - Chengqi Wang
- Center for Global Health and Infectious Diseases, Department of Global Health, University of South Florida, Tampa, FL, 33612, USA
| | - Min Liu
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA
- Department of Pathogen Biology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Xiaoying Liang
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA
| | - Hui Min
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA
| | - Qi Fan
- Dalian Institute of Biotechnology, Dalian, Liaoning, China
| | - Faiza Amber Siddiqui
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA
| | - Swamy Rakesh Adapa
- Center for Global Health and Infectious Diseases, Department of Global Health, University of South Florida, Tampa, FL, 33612, USA
| | - Xiaolian Li
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA
| | - Rays H Y Jiang
- Center for Global Health and Infectious Diseases, Department of Global Health, University of South Florida, Tampa, FL, 33612, USA
| | - Xiaoguang Chen
- Department of Pathogen Biology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Liwang Cui
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA
| | - Jun Miao
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA.
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Yu YS, Kim H, Kim KI, Baek SH. Epigenetic regulation of autophagy by histone-modifying enzymes under nutrient stress. Cell Death Differ 2023; 30:1430-1436. [PMID: 36997734 PMCID: PMC10244364 DOI: 10.1038/s41418-023-01154-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/16/2023] [Accepted: 03/20/2023] [Indexed: 04/01/2023] Open
Abstract
Autophagy is an evolutionarily conserved catabolic process that is induced in response to various stress factors in order to protect cells and maintain cellular homeostasis by degrading redundant components and dysfunctional organelles. Dysregulation of autophagy has been implicated in several conditions such as cancer, neurodegenerative diseases, and metabolic disorders. Although autophagy has been commonly considered as a cytoplasmic process, accumulating evidence has revealed that epigenetic regulation within the nucleus is also important for regulation of autophagy. In particular, when energy homeostasis is disrupted, for instance due to nutrient deprivation, cells increase autophagic activity at the transcriptional level, thereby also increasing the extent of overall autophagic flux. The transcription of genes associated with autophagy is strictly regulated by epigenetic factors through a network of histone-modifying enzymes along with histone modifications. A better understanding of the complex regulatory mechanisms of autophagy could reveal potential new therapeutic targets for autophagy-related diseases. In this review, we discuss the epigenetic regulation of autophagy in response to nutrient stress, focusing on histone-modifying enzymes and histone modifications.
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Affiliation(s)
- Young Suk Yu
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hyunkyung Kim
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, 02841, Republic of Korea.
- BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, 02841, Republic of Korea.
| | - Keun Il Kim
- Department of Biological Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
| | - Sung Hee Baek
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
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38
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Schibler AC, Jevtic P, Pegoraro G, Levy DL, Misteli T. Identification of epigenetic modulators as determinants of nuclear size and shape. eLife 2023; 12:e80653. [PMID: 37219077 PMCID: PMC10259489 DOI: 10.7554/elife.80653] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 05/04/2023] [Indexed: 05/24/2023] Open
Abstract
The shape and size of the human cell nucleus is highly variable among cell types and tissues. Changes in nuclear morphology are associated with disease, including cancer, as well as with premature and normal aging. Despite the very fundamental nature of nuclear morphology, the cellular factors that determine nuclear shape and size are not well understood. To identify regulators of nuclear architecture in a systematic and unbiased fashion, we performed a high-throughput imaging-based siRNA screen targeting 867 nuclear proteins including chromatin-associated proteins, epigenetic regulators, and nuclear envelope components. Using multiple morphometric parameters, and eliminating cell cycle effectors, we identified a set of novel determinants of nuclear size and shape. Interestingly, most identified factors altered nuclear morphology without affecting the levels of lamin proteins, which are known prominent regulators of nuclear shape. In contrast, a major group of nuclear shape regulators were modifiers of repressive heterochromatin. Biochemical and molecular analysis uncovered a direct physical interaction of histone H3 with lamin A mediated via combinatorial histone modifications. Furthermore, disease-causing lamin A mutations that result in disruption of nuclear shape inhibited lamin A-histone H3 interactions. Oncogenic histone H3.3 mutants defective for H3K27 methylation resulted in nuclear morphology abnormalities. Altogether, our results represent a systematic exploration of cellular factors involved in determining nuclear morphology and they identify the interaction of lamin A with histone H3 as an important contributor to nuclear morphology in human cells.
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Affiliation(s)
| | - Predrag Jevtic
- Department of Molecular Biology, University of WyomingLaramieUnited States
| | - Gianluca Pegoraro
- High Throughput Imaging Facility (HiTIF), National Cancer Institute, NIHBethesdaUnited States
| | - Daniel L Levy
- Department of Molecular Biology, University of WyomingLaramieUnited States
| | - Tom Misteli
- National Cancer InstituteBethesdaUnited States
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39
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Burlibasa L, Nicu AT, Chifiriuc MC, Medar C, Petrescu A, Jinga V, Stoica I. H3 histone methylation landscape in male urogenital cancers: from molecular mechanisms to epigenetic biomarkers and therapeutic targets. Front Cell Dev Biol 2023; 11:1181764. [PMID: 37228649 PMCID: PMC10203431 DOI: 10.3389/fcell.2023.1181764] [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: 03/07/2023] [Accepted: 04/27/2023] [Indexed: 05/27/2023] Open
Abstract
During the last decades, male urogenital cancers (including prostate, renal, bladder and testicular cancers) have become one of the most frequently encountered malignancies affecting all ages. While their great variety has promoted the development of various diagnosis, treatment and monitoring strategies, some aspects such as the common involvement of epigenetic mechanisms are still not elucidated. Epigenetic processes have come into the spotlight in the past years as important players in the initiation and progression of tumors, leading to a plethora of studies highlighting their potential as biomarkers for diagnosis, staging, prognosis, and even as therapeutic targets. Thus, fostering research on the various epigenetic mechanisms and their roles in cancer remains a priority for the scientific community. This review focuses on one of the main epigenetic mechanisms, namely, the methylation of the histone H3 at various sites and its involvement in male urogenital cancers. This histone modification presents a great interest due to its modulatory effect on gene expression, leading either to activation (e.g., H3K4me3, H3K36me3) or repression (e.g., H3K27me3, H3K9me3). In the last few years, growing evidence has demonstrated the aberrant expression of enzymes that methylate/demethylate histone H3 in cancer and inflammatory diseases, that might contribute to the initiation and progression of such disorders. We highlight how these particular epigenetic modifications are emerging as potential diagnostic and prognostic biomarkers or targets for the treatment of urogenital cancers.
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Affiliation(s)
| | | | - Mariana Carmen Chifiriuc
- Faculty of Biology, University of Bucharest, Bucharest, Romania
- Academy of Romanian Scientists, Bucharest, Romania
- Romanian Academy, Bucharest, Romania
| | - Cosmin Medar
- University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
- Clinical Hospital “Prof. dr Theodor Burghele”, Bucharest, Romania
| | - Amelia Petrescu
- Clinical Hospital “Prof. dr Theodor Burghele”, Bucharest, Romania
| | - Viorel Jinga
- Academy of Romanian Scientists, Bucharest, Romania
- University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
- Clinical Hospital “Prof. dr Theodor Burghele”, Bucharest, Romania
| | - Ileana Stoica
- Faculty of Biology, University of Bucharest, Bucharest, Romania
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40
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Moena D, Vargas E, Montecino M. Epigenetic regulation during 1,25-dihydroxyvitamin D 3-dependent gene transcription. VITAMINS AND HORMONES 2023; 122:51-74. [PMID: 36863801 DOI: 10.1016/bs.vh.2023.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Multiple evidence accumulated over the years, demonstrates that vitamin D-dependent physiological control in vertebrates occurs primarily through the regulation of target gene transcription. In addition, there has been an increasing appreciation of the role of the chromatin organization of the genome on the ability of the active form of vitamin D, 1,25(OH)2D3, and its specific receptor VDR to regulate gene expression. Chromatin structure in eukaryotic cells is principally modulated through epigenetic mechanisms including, but not limited to, a wide number of post-translational modifications of histone proteins and ATP-dependent chromatin remodelers, which are operative in different tissues during response to physiological cues. Hence, there is necessity to understand in depth the epigenetic control mechanisms that operate during 1,25(OH)2D3-dependent gene regulation. This chapter provides a general overview about epigenetic mechanisms functioning in mammalian cells and discusses how some of these mechanisms represent important components during transcriptional regulation of the model gene system CYP24A1 in response to 1,25(OH)2D3.
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Affiliation(s)
- Daniel Moena
- School of Bachelor in Science, Faculty of Life Sciences, Universidad Andres Bello, Concepcion, Chile
| | - Esther Vargas
- School of Medicine, Universidad Andres Bello, Santiago, Chile
| | - Martin Montecino
- Institute of Biomedical Sciences, Faculty of Medicine, Universidad Andres Bello, Santiago, Chile; Millenium Institute Center for Genome Regulation (CRG), Santiago, Chile.
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41
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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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42
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Ding M, Cho E, Chen Z, Park SW, Lee TH. ( S)-2-(Cyclobutylamino)- N-(3-(3,4-dihydroisoquinolin-2(1 H)-yl)-2-hydroxypropyl)isonicotinamide Attenuates RANKL-Induced Osteoclast Differentiation by Inhibiting NF-κB Nuclear Translocation. Int J Mol Sci 2023; 24:ijms24054327. [PMID: 36901758 PMCID: PMC10002170 DOI: 10.3390/ijms24054327] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/15/2023] [Accepted: 02/20/2023] [Indexed: 02/24/2023] Open
Abstract
Osteoporosis is a common skeletal disease; however, effective pharmacological treatments still need to be discovered. This study aimed to identify new drug candidates for the treatment of osteoporosis. Here, we investigated the effect of EPZ compounds, protein arginine methyltransferase 5 (PRMT5) inhibitors, on RANKL-induced osteoclast differentiation via molecular mechanisms by in vitro experiments. EPZ015866 attenuated RANKL-induced osteoclast differentiation, and its inhibitory effect was more significant than EPZ015666. EPZ015866 suppressed the F-actin ring formation and bone resorption during osteoclastogenesis. In addition, EPZ015866 significantly decreased the protein expression of Cathepsin K, NFATc1, and PU.1 compared with the EPZ015666 group. Both EPZ compounds inhibited the nuclear translocation of NF-κB by inhibiting the dimethylation of the p65 subunit, which eventually prevented osteoclast differentiation and bone resorption. Hence, EPZ015866 may be a potential drug candidate for the treatment of osteoporosis.
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Affiliation(s)
- Mina Ding
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, Gwangju 61186, Republic of Korea
| | - Eunjin Cho
- Department of Oral Biochemistry, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Zhihao Chen
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, Gwangju 61186, Republic of Korea
| | - Sang-Wook Park
- Department of Oral Biochemistry, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Tae-Hoon Lee
- Department of Oral Biochemistry, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea
- Correspondence:
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43
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Scagnoli F, Palma A, Favia A, Scuoppo C, Illi B, Nasi S. A New Insight into MYC Action: Control of RNA Polymerase II Methylation and Transcription Termination. Biomedicines 2023; 11:biomedicines11020412. [PMID: 36830948 PMCID: PMC9952900 DOI: 10.3390/biomedicines11020412] [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: 12/13/2022] [Revised: 01/16/2023] [Accepted: 01/26/2023] [Indexed: 02/01/2023] Open
Abstract
MYC oncoprotein deregulation is a common catastrophic event in human cancer and limiting its activity restrains tumor development and maintenance, as clearly shown via Omomyc, an MYC-interfering 90 amino acid mini-protein. MYC is a multifunctional transcription factor that regulates many aspects of transcription by RNA polymerase II (RNAPII), such as transcription activation, pause release, and elongation. MYC directly associates with Protein Arginine Methyltransferase 5 (PRMT5), a protein that methylates a variety of targets, including RNAPII at the arginine residue R1810 (R1810me2s), crucial for proper transcription termination and splicing of transcripts. Therefore, we asked whether MYC controls termination as well, by affecting R1810me2S. We show that MYC overexpression strongly increases R1810me2s, while Omomyc, an MYC shRNA, or a PRMT5 inhibitor and siRNA counteract this phenomenon. Omomyc also impairs Serine 2 phosphorylation in the RNAPII carboxyterminal domain, a modification that sustains transcription elongation. ChIP-seq experiments show that Omomyc replaces MYC and reshapes RNAPII distribution, increasing occupancy at promoter and termination sites. It is unclear how this may affect gene expression. Transcriptomic analysis shows that transcripts pivotal to key signaling pathways are both up- or down-regulated by Omomyc, whereas genes directly controlled by MYC and belonging to a specific signature are strongly down-regulated. Overall, our data point to an MYC/PRMT5/RNAPII axis that controls termination via RNAPII symmetrical dimethylation and contributes to rewiring the expression of genes altered by MYC overexpression in cancer cells. It remains to be clarified which role this may have in tumor development.
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Affiliation(s)
- Fiorella Scagnoli
- IBPM—CNR, Biology and Biotechnology Department, Sapienza University, 00185 Rome, Italy
- Correspondence: (F.S.); (B.I.); (S.N.)
| | - Alessandro Palma
- Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy
| | - Annarita Favia
- IBPM—CNR, Biology and Biotechnology Department, Sapienza University, 00185 Rome, Italy
| | - Claudio Scuoppo
- Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
| | - Barbara Illi
- IBPM—CNR, Biology and Biotechnology Department, Sapienza University, 00185 Rome, Italy
- Correspondence: (F.S.); (B.I.); (S.N.)
| | - Sergio Nasi
- IBPM—CNR, Biology and Biotechnology Department, Sapienza University, 00185 Rome, Italy
- Correspondence: (F.S.); (B.I.); (S.N.)
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44
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Histone methylation in pre-cancerous liver diseases and hepatocellular carcinoma: recent overview. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2023; 25:1594-1605. [PMID: 36650321 DOI: 10.1007/s12094-023-03078-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 01/07/2023] [Indexed: 01/19/2023]
Abstract
Hepatocellular carcinoma (HCC) is the prevalent form of liver cancer in adults and the fourth most common cause of cancer-related death worldwide. HCC predominantly arises in the context of cirrhosis as a result of chronic liver disease, injury and inflammation. Full-blown HCC has poor prognosis because it is highly aggressive and resistant to therapy. Consequently, interventions that can prevent or restrain HCC emergence from pre-cancerous diseased liver are a desirable strategy. Histone methylation is a dynamic, reversible epigenetic modification involving the addition or removal of methyl groups from lysine, arginine or glutamine residues. Aberrant activity of histone methylation writers, erases and readers has been implicated in several cancer types, including HCC. In this review, we provide an overview of research on the role of histone methylation in pre-cancerous and cancerous HCC published over the last 5 years. In particular, we present the evidence linking environmental factors such as diet, viral infections and carcinogenic agents with dysregulation of histone methylation during liver cancer progression with the aim to highlight future therapeutic possibilities.
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Roy A, Niharika, Chakraborty S, Mishra J, Singh SP, Patra SK. Mechanistic aspects of reversible methylation modifications of arginine and lysine of nuclear histones and their roles in human colon cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 197:261-302. [PMID: 37019596 DOI: 10.1016/bs.pmbts.2023.01.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/08/2023]
Abstract
Developmental proceedings and maintenance of cellular homeostasis are regulated by the precise orchestration of a series of epigenetic events that eventually control gene expression. DNA methylation and post-translational modifications (PTMs) of histones are well-characterized epigenetic events responsible for fine-tuning gene expression. PTMs of histones bear molecular logic of gene expression at chromosomal territory and have become a fascinating field of epigenetics. Nowadays, reversible methylation on histone arginine and lysine is gaining increasing attention as a significant PTM related to reorganizing local nucleosomal structure, chromatin dynamics, and transcriptional regulation. It is now well-accepted and reported that histone marks play crucial roles in colon cancer initiation and progression by encouraging abnormal epigenomic reprogramming. It is becoming increasingly clear that multiple PTM marks at the N-terminal tails of the core histones cross-talk with one another to intricately regulate DNA-templated biological processes such as replication, transcription, recombination, and damage repair in several malignancies, including colon cancer. These functional cross-talks provide an additional layer of message, which spatiotemporally fine-tunes the overall gene expression regulation. Nowadays, it is evident that several PTMs instigate colon cancer development. How colon cancer-specific PTM patterns or codes are generated and how they affect downstream molecular events are uncovered to some extent. Future studies would address more about epigenetic communication, and the relationship between histone modification marks to define cellular functions in depth. This chapter will comprehensively highlight the importance of histone arginine and lysine-based methylation modifications and their functional cross-talk with other histone marks from the perspective of colon cancer development.
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Song Y, Zhang Y, Xie S, Song X. Screening and diagnosis of triple negative breast cancer based on rapid metabolic fingerprinting by conductive polymer spray ionization mass spectrometry and machine learning. Front Cell Dev Biol 2022; 10:1075810. [PMID: 36589750 PMCID: PMC9798417 DOI: 10.3389/fcell.2022.1075810] [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: 10/20/2022] [Accepted: 11/22/2022] [Indexed: 12/23/2022] Open
Abstract
We present the use of conductive spray polymer ionization mass spectrometry (CPSI-MS) combined with machine learning (ML) to rapidly gain the metabolic fingerprint from 1 μl liquid extraction from the biopsied tissue of triple-negative breast cancer (TNBC) in China. The 76 discriminative metabolite markers are verified at the primary carcinoma site and can also be successfully tracked in the serum. The Lasso classifier featured with 15- and 22-metabolites detected by CPSI-MS achieve a sensitivity of 88.8% for rapid serum screening and a specificity of 91.1% for tissue diagnosis, respectively. Finally, the expression levels of their corresponding upstream enzymes and transporters have been initially confirmed. In general, CPSI-MS/ML serves as a cost-effective tool for the rapid screening, diagnosis, and precise characterization for the TNBC metabolism reprogramming in the clinical practice.
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Affiliation(s)
- Yaoyao Song
- Department of General Surgery, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, China,Department of Burn and Plastic Surgery, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yan Zhang
- Department of General Surgery, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Songhai Xie
- Department of Chemistry, Fudan University, Shanghai, China
| | - Xiaowei Song
- Department of Chemistry, Fudan University, Shanghai, China,*Correspondence: Xiaowei Song,
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Qin J, Xu J. Arginine methylation in the epithelial-to-mesenchymal transition. FEBS J 2022; 289:7292-7303. [PMID: 34358413 PMCID: PMC10181118 DOI: 10.1111/febs.16152] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/23/2021] [Accepted: 08/04/2021] [Indexed: 01/13/2023]
Abstract
Epithelial cells acquire mesenchymal characteristics during embryonic development, wound healing, fibrosis, and in cancer in a processed termed epithelial-to-mesenchymal transition (EMT). Regulatory networks of EMT are controlled by post-transcriptional, translational, and post-translational mechanisms, in which arginine methylation is critically involved. Here, we review arginine methylation-dependent mechanisms that regulate EMT in the aspects of signaling, transcriptional, and splicing regulation.
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Affiliation(s)
- Jian Qin
- Central laboratory, Renmin Hospital of Wuhan University, China
| | - Jian Xu
- Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.,Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA.,Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Sauter C, Simonet J, Guidez F, Dumétier B, Pernon B, Callanan M, Bastie JN, Aucagne R, Delva L. Protein Arginine Methyltransferases as Therapeutic Targets in Hematological Malignancies. Cancers (Basel) 2022; 14:5443. [PMID: 36358861 PMCID: PMC9657843 DOI: 10.3390/cancers14215443] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/31/2022] [Accepted: 11/01/2022] [Indexed: 08/02/2023] Open
Abstract
Arginine methylation is a common post-translational modification affecting protein activity and the transcription of target genes when methylation occurs on histone tails. There are nine protein arginine methyltransferases (PRMTs) in mammals, divided into subgroups depending on the methylation they form on a molecule of arginine. During the formation and maturation of the different types of blood cells, PRMTs play a central role by controlling cell differentiation at the transcriptional level. PRMT enzymatic activity is necessary for many cellular processes in hematological malignancies, such as the activation of cell cycle and proliferation, inhibition of apoptosis, DNA repair processes, RNA splicing, and transcription by methylating histone tails' arginine. Chemical tools have been developed to inhibit the activity of PRMTs and have been tested in several models of hematological malignancies, including primary samples from patients, xenografts into immunodeficient mice, mouse models, and human cell lines. They show a significant effect by reducing cell viability and increasing the overall survival of mice. PRMT5 inhibitors have a strong therapeutic potential, as phase I clinical trials in hematological malignancies that use these molecules show promising results, thus, underlining PRMT inhibitors as useful therapeutic tools for cancer treatment in the future.
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Affiliation(s)
- Camille Sauter
- Inserm U1231, Team Epi2THM, LipSTIC Labex, UFR des Sciences de Santé, Université de Bourgogne, Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - John Simonet
- Inserm U1231, Team Epi2THM, LipSTIC Labex, UFR des Sciences de Santé, Université de Bourgogne, Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Fabien Guidez
- Inserm U1231, Team Epi2THM, LipSTIC Labex, UFR des Sciences de Santé, Université de Bourgogne, Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Baptiste Dumétier
- Inserm U1231, Team Epi2THM, LipSTIC Labex, UFR des Sciences de Santé, Université de Bourgogne, Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Baptiste Pernon
- Inserm U1231, Team Epi2THM, LipSTIC Labex, UFR des Sciences de Santé, Université de Bourgogne, Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Mary Callanan
- Inserm U1231, Team Epi2THM, LipSTIC Labex, UFR des Sciences de Santé, Université de Bourgogne, Université Bourgogne Franche-Comté, 21000 Dijon, France
- Unit for Innovation in Genetics and Epigenetic in Oncology (IGEO)/CRIGEN Core Facility, University Hospital François Mitterrand, 21000 Dijon, France
| | - Jean-Noël Bastie
- Inserm U1231, Team Epi2THM, LipSTIC Labex, UFR des Sciences de Santé, Université de Bourgogne, Université Bourgogne Franche-Comté, 21000 Dijon, France
- Department of Clinical Hematology, University Hospital François Mitterrand, 21000 Dijon, France
| | - Romain Aucagne
- Inserm U1231, Team Epi2THM, LipSTIC Labex, UFR des Sciences de Santé, Université de Bourgogne, Université Bourgogne Franche-Comté, 21000 Dijon, France
- Unit for Innovation in Genetics and Epigenetic in Oncology (IGEO)/CRIGEN Core Facility, University Hospital François Mitterrand, 21000 Dijon, France
| | - Laurent Delva
- Inserm U1231, Team Epi2THM, LipSTIC Labex, UFR des Sciences de Santé, Université de Bourgogne, Université Bourgogne Franche-Comté, 21000 Dijon, France
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Ling Q, Liao J, Liu X, Zhou Y, Qian Y. Genome-Wide Identification of Maize Protein Arginine Methyltransferase Genes and Functional Analysis of ZmPRMT1 Reveal Essential Roles in Arabidopsis Flowering Regulation and Abiotic Stress Tolerance. Int J Mol Sci 2022; 23:12793. [PMID: 36361583 PMCID: PMC9655960 DOI: 10.3390/ijms232112793] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/17/2022] [Accepted: 10/20/2022] [Indexed: 10/29/2023] Open
Abstract
Histone methylation, as one of the important epigenetic regulatory mechanisms, plays a significant role in growth and developmental processes and stress responses of plants, via altering the methylation status or ratio of arginine and lysine residues of histone tails, which can affect the regulation of gene expression. Protein arginine methyltransferases (PRMTs) have been revealed to be responsible for histone methylation of specific arginine residues in plants, which is important for maintaining pleiotropic development and adaptation to abiotic stresses in plants. Here, for the first time, a total of eight PRMT genes in maize have been identified and characterized in this study, named as ZmPRMT1-8. According to comparative analyses of phylogenetic relationship and structural characteristics among PRMT gene family members from several representative species, all maize 8 PRMT proteins were categorized into three distinct subfamilies. Further, schematic structure and chromosome location analyses displayed evolutionarily conserved structure features and an unevenly distribution on maize chromosomes of ZmPRMT genes, respectively. The expression patterns of ZmPRMT genes in different tissues and under various abiotic stresses (heat, drought, and salt) were determined. The expression patterns of ZmPRMT genes indicated that they play a role in regulating growth and development and responses to abiotic stress. Eventually, to verify the biological roles of ZmPRMT genes, the transgenic Arabidopsis plants overexpressing ZmPRMT1 gene was constructed as a typical representative. The results demonstrated that overexpression of ZmPRMT1 can promote earlier flowering time and confer enhanced heat tolerance in transgenic Arabidopsis. Taken together, our results are the first to report the roles of ZmPRMT1 gene in regulating flowering time and resisting heat stress response in plants and will provide a vital theoretical basis for further unraveling the functional roles and epigenetic regulatory mechanism of ZmPRMT genes in maize growth, development and responses to abiotic stresses.
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Affiliation(s)
| | | | | | | | - Yexiong Qian
- Anhui Provincial Key Laboratory of Conservation and Exploitation of Important Biological Resources, College of Life Sciences, Anhui Normal University, Wuhu 241000, China
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Quan Y, Zhang X, Wang M, Ping H. Histone lysine methylation patterns in prostate cancer microenvironment infiltration: Integrated bioinformatic analysis and histological validation. Front Oncol 2022; 12:981226. [PMID: 36237332 PMCID: PMC9552767 DOI: 10.3389/fonc.2022.981226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022] Open
Abstract
Background Epigenetic reprogramming through dysregulated histone lysine methylation (HLM) plays a crucial role in prostate cancer (PCa) progression. This study aimed to comprehensively evaluate HLM modification patterns in PCa microenvironment infiltration. Materials and methods Ninety-one HLM regulators in The Cancer Genome Atlas (TCGA) dataset were analyzed using bioinformatics. Differentially expressed genes (DEGs) and survival analyses were performed using TCGA-PRAD clinicopathologic and follow-up information. Consensus clustering analysis divided patients into subgroups. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the DEGs. Tumor mutation burden (TMB) and tumor microenvironment (TME) cell infiltration were evaluated in different HLM clusters. Quantitative real-time PCR (qPCR) analysis assessed HLM regulators in clinical PCa tissues. Results The tumor vs. normal (TN), Gleason score (GS) > 7 vs. GS < 7, pathological T stage (pT) = 2 vs. pT = 3, and TP53 mutation vs. wild-type comparisons using TCGA-PRAD dataset revealed 3 intersecting HLM regulators (EZH2, NSD2, and KMT5C) that were consistently upregulated in advanced PCa (GS > 7, pT3, HR > 1, and TP53 mutation) (P < 0.05) and verified in clinical PCa tissues. Consensus clustering analysis revealed three distinct HLM modification patterns (HLMclusters). However, no significant differences in recurrence-free survival (RFS) rates were found among the groups (P > 0.05). We screened 189 HLM phenotype-related genes that overlapped in the pairwise comparisons of HLMclusters and P < 0.01 in the Cox regression analysis. Three distinct subgroups (geneClusters) were revealed based on the 189 genes, in which cluster A involved the most advanced PCa (PSA > 10, T3-4, GS8-10, and biochemical recurrence) and the poorest RFS. The HLM score (HLMscore) was calculated by principal component analysis (PCA) of HLM phenotype-related genes that have positive predictive value for RFS (P < 0.001) and immune therapy responses (in the CTLA4-positive and -negative responses accompanied by a PD1-negative response). Conclusion We comprehensively evaluated HLM regulators in the PCa microenvironment using TCGA-PRAD, revealing a nonnegligible role of HLM patterns in PCa complexity and heterogeneity. Elucidating the effects of HLM regulators in PCa may enhance prognostics, aggressiveness assessments, and immunotherapy strategies.
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Affiliation(s)
- Yongjun Quan
- Department of Urology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Xiaodong Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Mingdong Wang
- Department of Urology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Hao Ping
- Department of Urology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University & Capital Medical University, Beijing Tongren Hospital, Beijing, China
- *Correspondence: Hao Ping,
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