美国贝勒医学院Margaret A. Goodell团队近日取得一项新成果。他们研究发现DNMT3A的无序N端结构域对H2AK119ub的识别是出生后发育所必需的。该项工作2022年5月9日在线发表于《自然—遗传学》杂志上。

在这里，研究人员报道了长亚型DNMT3A1，而不是短亚型DNMT3A2，对小鼠出生后发育至关重要。DNMT3A1结合并调节大脑中的二价神经发育基因。值得注意的是，Dnmt3a1基因敲除的围产期致死率可以通过DNMT3A1在神经系统的表达恢复而得到部分拯救。研究人员进一步表明，DNMT3A1的内在无序的N端是正常发育和DNMT3A1富集区域的DNA甲基化所必需的。从机制上讲，嵌入在N末端推定的α-螺旋中的泛素相互作用基序与单泛素化的组蛋白H2AK119结合，可能介导DNMT3A1向Polycomb调节区域的募集。这些数据证明了DNMT3A1亚型在小鼠出生后发育中的特异性作用，并揭示了N末端是DNMT3A1染色质占据和神经系统功能的必要调节域。

据悉，DNA甲基转移酶3a (DNMT3A)在哺乳动物的发育中起着至关重要的作用。DNMT3A的两种异构体从干细胞到体细胞组织都有不同的表达，但它们各自的功能在很大程度上仍不明确。

附：英文原文

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

Author: Gu, Tianpeng, Hao, Dapeng, Woo, Junsung, Huang, Teng-Wei, Guo, Lei, Lin, Xueqiu, Guzman, Anna G., Tovy, Ayala, Rosas, Carina, Jeong, Mira, Zhou, Yubin, Deneen, Benjamin, Huang, Yun, Li, Wei, Goodell, Margaret A.

Issue&Volume: 2022-05-09

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. The long isoform of DNMT3A is essential for mouse postnatal development and regulates bivalent genes in the brain, likely via a PRC1-mediated mechanism.

DOI: 10.1038/s41588-022-01063-6

Source: https://www.nature.com/articles/s41588-022-01063-6