DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

Wendan Ren, Huitao Fan, Sara A. Grimm, Jae Jin Kim, Linhui Li, Yiran Guo, Christopher James Petell, Xiao-Feng Tan, Zhi-Min Zhang, John P. Coan, Jiekai Yin, Dae In Kim, Linfeng Gao, Ling Cai, Nelli Khudaverdyan, Burak Çetin, Dinshaw J. Patel, Yinsheng Wang, Qiang Cui, Brian D. Strahl, Or Gozani, Kyle M. Miller, Seán E. O’Leary, Paul A. Wade, Gang Greg Wang () and Jikui Song ()
Additional contact information
Wendan Ren: University of California
Huitao Fan: University of North Carolina at Chapel Hill School of Medicine
Sara A. Grimm: National Institute of Environmental Health Sciences, Research Triangle Park
Jae Jin Kim: University of Texas at Austin
Linhui Li: University of California
Yiran Guo: University of North Carolina at Chapel Hill School of Medicine
Christopher James Petell: University of North Carolina at Chapel Hill School of Medicine
Xiao-Feng Tan: University of California
Zhi-Min Zhang: University of California
John P. Coan: Stanford University
Jiekai Yin: University of California
Dae In Kim: University of Texas at Austin
Linfeng Gao: University of California
Ling Cai: University of North Carolina at Chapel Hill School of Medicine
Nelli Khudaverdyan: University of California
Burak Çetin: University of California, Riverside
Dinshaw J. Patel: Memorial Sloan Kettering Cancer Center
Yinsheng Wang: University of California
Qiang Cui: Boston University
Brian D. Strahl: University of North Carolina at Chapel Hill School of Medicine
Or Gozani: Stanford University
Kyle M. Miller: University of Texas at Austin
Seán E. O’Leary: University of California
Paul A. Wade: National Institute of Environmental Health Sciences, Research Triangle Park
Gang Greg Wang: University of North Carolina at Chapel Hill School of Medicine
Jikui Song: University of California

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract DNA methylation and trimethylated histone H4 Lysine 20 (H4K20me3) constitute two important heterochromatin-enriched marks that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two chromatin modifications crosstalk. Here, we report that DNA methyltransferase 1 (DNMT1) specifically ‘recognizes’ H4K20me3 via its first bromo-adjacent-homology domain (DNMT1BAH1). Engagement of DNMT1BAH1-H4K20me3 ensures heterochromatin targeting of DNMT1 and DNA methylation at LINE-1 retrotransposons, and cooperates with the previously reported readout of histone H3 tail modifications (i.e., H3K9me3 and H3 ubiquitylation) by the RFTS domain to allosterically regulate DNMT1’s activity. Interplay between RFTS and BAH1 domains of DNMT1 profoundly impacts DNA methylation at both global and focal levels and genomic resistance to radiation-induced damage. Together, our study establishes a direct link between H4K20me3 and DNA methylation, providing a mechanism in which multivalent recognition of repressive histone modifications by DNMT1 ensures appropriate DNA methylation patterning and genomic stability.

Date: 2021
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DOI: 10.1038/s41467-021-22665-4

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