Department of Biochemistry, University of California, Riverside, CA 92521.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599.
Proc Natl Acad Sci U S A. 2020 Aug 4;117(31):18439-18447. doi: 10.1073/pnas.2009316117. Epub 2020 Jul 16.
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 stem cells and profoundly impairs the global DNA methylation and genomic stability. Together, this study reveals a previously unappreciated pathway through which H3K9me3 directly reinforces DNMT1-mediated maintenance DNA methylation.
在哺乳动物中，抑制性组蛋白修饰，如组蛋白 H3 赖氨酸 9 的三甲基化（H3K9me3），通常与 DNA 甲基化共存，产生更稳定和沉默的染色质状态。然而，这些表观遗传修饰如何相互作用仍然难以捉摸。在这里，通过结构和生化特性分析，我们鉴定出维持 DNA 甲基转移酶 DNMT1 的复制焦点靶向序列（RFTS）结构域作为 H3K9me3/H3Ub 的特定阅读器，该结构域与已知结合泛素化 H3（H3Ub）的模块有关，其识别模式不同于典型的三甲基赖氨酸阅读器。RFTS 与 H3K9me3Ub 之间相互作用的破坏会影响干细胞中 DNMT1 的定位，并严重损害全局 DNA 甲基化和基因组稳定性。总之，这项研究揭示了一条以前未被重视的途径，即 H3K9me3 直接增强了 DNMT1 介导的维持性 DNA 甲基化。
