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DNMT3A 无序的 N 端结构域识别 H2AK119ub，并对出生后发育至关重要。

The disordered N-terminal domain of DNMT3A recognizes H2AK119ub and is required for postnatal development.

机构信息

Molecular and Cellular Biology Department, Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA.

Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.

出版信息

Nat Genet. 2022 May;54(5):625-636. doi: 10.1038/s41588-022-01063-6. Epub 2022 May 9.

DOI:10.1038/s41588-022-01063-6
PMID:35534561
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9295050/
Abstract

DNA methyltransferase 3a (DNMT3A) plays a crucial role during mammalian development. Two isoforms of DNMT3A are differentially expressed from stem cells to somatic tissues, but their individual functions remain largely uncharacterized. Here we report that the long isoform DNMT3A1, but not the short DNMT3A2, is essential for mouse postnatal development. DNMT3A1 binds to and regulates bivalent neurodevelopmental genes in the brain. Strikingly, Dnmt3a1 knockout perinatal lethality could be partially rescued by DNMT3A1 restoration in the nervous system. We further show that the intrinsically disordered N terminus of DNMT3A1 is required for normal development and DNA methylation at DNMT3A1-enriched regions. Mechanistically, a ubiquitin-interacting motif embedded in a putative α-helix within the N terminus binds to mono-ubiquitinated histone H2AK119, probably mediating recruitment of DNMT3A1 to Polycomb-regulated regions. These data demonstrate an isoform-specific role for DNMT3A1 in mouse postnatal development and reveal the N terminus as a necessary regulatory domain for DNMT3A1 chromatin occupancy and functions in the nervous system.

摘要

DNA 甲基转移酶 3A（DNMT3A）在哺乳动物发育过程中起着至关重要的作用。DNMT3A 有两种异构体，从干细胞到体细胞组织中差异表达，但它们的各自功能在很大程度上仍未被阐明。在这里，我们报告长异构体 DNMT3A1，但不是短异构体 DNMT3A2，对于小鼠出生后的发育是必不可少的。DNMT3A1 结合并调节大脑中的双价神经发育基因。引人注目的是，Dnmt3a1 基因敲除的围产期致死率可以通过神经组织中 DNMT3A1 的恢复部分挽救。我们进一步表明，DNMT3A1 的固有无序 N 端对于正常发育和富含 DNMT3A1 的区域的 DNA 甲基化是必需的。从机制上讲，N 端中一个潜在的 α-螺旋内的一个泛素相互作用基序与单泛素化组蛋白 H2AK119 结合，可能介导 DNMT3A1 向多梳蛋白调控区域的募集。这些数据表明，DNMT3A1 在小鼠出生后的发育中具有异构体特异性作用，并揭示了 N 端作为 DNMT3A1 染色质占据和在神经系统中发挥功能的必要调节域。

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