Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation
Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation
ABSTRACT In mammals, repressive histone modifications such as trimethylation of histone H3 Lys9 (H3K9me3), frequently coexist with DNA methylation, producing a more stable and silenced chromatin state. However, it remains elusive how these epigenetic modifications crosstalk. Here, through structural and biochemical characterizations, we identified the replication foci targeting sequence (RFTS) domain of maintenance DNA methyltransferase DNMT1, a module known to bind the ubiquitylated H3 (H3Ub), as a specific reader for H3K9me3/H3Ub, with the recognition mode distinct from the typical trimethyl-lysine reader. Disruption of the interaction between RFTS and the H3K9me3Ub affects the localization of DNMT1 in ES cells and profoundly impairs the global DNA methylation and genomic stability. Together, this study reveals a previously unappreciated pathway through which H3K9me3 directly regulates DNMT1-mediated maintenance DNA methylation.
Detrick Brittany、Miller Kyle M.、Wang Gang Greg、Guo Yiran、Li Linhui、Coan John P.、Cai Ling、Cui Qiang、Petell Christopher James、?etin Burak、Song Jikui、Gao Linfeng、Gozani Or、Strahl Brian D.、O?ˉLeary Se¨￠n E.、Kim Jae Jin、Yin Jiekai、Ren Wendan、Patel Dinshaw J.、Grimm Sara A、Wang Yinsheng、Fan Huitao、Zhang Zhi-Min、Tan Xiao-Feng、Wade Paul A.
Department of Biochemistry, University of CaliforniaDepartment of Molecular Biosciences, LIVESTRONG Cancer Institute of the Dell Medical School, Institute for Cellular and Molecular Biology, University of Texas at AustinLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine||Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of MedicineLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine||Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of MedicineDepartment of Biochemistry, University of CaliforniaDepartment of Biology, Stanford UniversityLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine||Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of MedicineDepartments of Chemistry, Physics and Biomedical Engineering, Boston UniversityLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine||Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of MedicineCell, Molecular, and Developmental Biology Graduate Program, University of CaliforniaDepartment of Biochemistry, University of California||Environmental Toxicology Graduate Program, University of CaliforniaEnvironmental Toxicology Graduate Program, University of CaliforniaDepartment of Biology, Stanford UniversityLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine||Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of MedicineDepartment of Biochemistry, University of California||Cell, Molecular, and Developmental Biology Graduate Program, University of CaliforniaDepartment of Molecular Biosciences, LIVESTRONG Cancer Institute of the Dell Medical School, Institute for Cellular and Molecular Biology, University of Texas at AustinEnvironmental Toxicology Graduate Program, University of CaliforniaDepartment of Biochemistry, University of CaliforniaStructural Biology Program, Memorial Sloan Kettering Cancer CenterDivision of Intramural Research, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle ParkEnvironmental Toxicology Graduate Program, University of California||Department of Chemistry, University of CaliforniaLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine||Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of MedicineDepartment of Biochemistry, University of CaliforniaDepartment of Biochemistry, University of CaliforniaDivision of Intramural Research, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park
分子生物学遗传学生物化学
Detrick Brittany,Miller Kyle M.,Wang Gang Greg,Guo Yiran,Li Linhui,Coan John P.,Cai Ling,Cui Qiang,Petell Christopher James,?etin Burak,Song Jikui,Gao Linfeng,Gozani Or,Strahl Brian D.,O?ˉLeary Se¨￠n E.,Kim Jae Jin,Yin Jiekai,Ren Wendan,Patel Dinshaw J.,Grimm Sara A,Wang Yinsheng,Fan Huitao,Zhang Zhi-Min,Tan Xiao-Feng,Wade Paul A..Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation[EB/OL].(2025-03-28)[2025-05-31].https://www.biorxiv.org/content/10.1101/2020.04.27.064493.点此复制
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