Ren Wendan, Fan Huitao, Grimm Sara A, Kim Jae Jin, Li Linhui, Guo Yiran, Petell Christopher James, Tan Xiao-Feng, Zhang Zhi-Min, Coan John P, Yin Jiekai, Kim Dae In, Gao Linfeng, Cai Ling, Khudaverdyan Nelli, Çetin Burak, Patel Dinshaw J, Wang Yinsheng, Cui Qiang, Strahl Brian D, Gozani Or, Miller Kyle M, O'Leary Seán E, Wade Paul A, Wang Gang Greg, Song Jikui
Department of Biochemistry, University of California, Riverside, CA, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Nat Commun. 2021 May 3;12(1):2490. doi: 10.1038/s41467-021-22665-4.
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 (DNMT1). Engagement of DNMT1-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.
DNA甲基化和组蛋白H4赖氨酸20三甲基化（H4K20me3）构成了两种重要的富含异染色质的标记，它们经常协同作用以沉默哺乳动物基因组中的重复元件。然而，这两种染色质修饰如何相互作用仍不清楚。在此，我们报告DNA甲基转移酶1（DNMT1）通过其第一个溴相邻同源结构域（DNMT1）特异性地“识别”H4K20me3。DNMT1-H4K20me3的结合确保了DNMT1在异染色质上的定位以及LINE-1逆转座子处的DNA甲基化，并与先前报道的RFTS结构域对组蛋白H3尾部修饰（即H3K9me3和H3泛素化）的识别协同作用，以变构调节DNMT1的活性。DNMT1的RFTS和BAH1结构域之间的相互作用在全局和局部水平上都对DNA甲基化以及基因组对辐射诱导损伤的抗性产生深远影响。总之，我们的研究建立了H4K20me3与DNA甲基化之间的直接联系，提供了一种机制，即DNMT1对抑制性组蛋白修饰的多价识别确保了适当的DNA甲基化模式和基因组稳定性。
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