Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK.
Centre for Trophoblast Research, University of Cambridge, Cambridge, CB2 3EG, UK.
Nat Commun. 2019 Apr 23;10(1):1884. doi: 10.1038/s41467-019-09713-w.
DNA methyltransferases (DNMTs) deposit DNA methylation, which regulates gene expression and is essential for mammalian development. Histone post-translational modifications modulate the recruitment and activity of DNMTs. The PWWP domains of DNMT3A and DNMT3B are posited to interact with histone 3 lysine 36 trimethylation (H3K36me3); however, the functionality of this interaction for DNMT3A remains untested in vivo. Here we present a mouse model carrying a D329A point mutation in the DNMT3A PWWP domain. The mutation causes dominant postnatal growth retardation. At the molecular level, it results in progressive DNA hypermethylation across domains marked by H3K27me3 and bivalent chromatin, and de-repression of developmental regulatory genes in adult hypothalamus. Evaluation of non-CpG methylation, a marker of de novo methylation, further demonstrates the altered recruitment and activity of DNMT3A at bivalent domains. This work provides key molecular insights into the function of the DNMT3A-PWWP domain and role of DNMT3A in regulating postnatal growth.
DNA 甲基转移酶 (DNMTs) 会使 DNA 甲基化，这对于基因表达的调控以及哺乳动物的发育是必不可少的。组蛋白的翻译后修饰可以调节 DNMTs 的募集和活性。DNMT3A 和 DNMT3B 的 PWWP 结构域被假定与组蛋白 3 赖氨酸 36 三甲基化 (H3K36me3) 相互作用；然而，这种相互作用对于 DNMT3A 在体内的功能仍然没有得到测试。在这里，我们介绍了一种携带 DNMT3A PWWP 结构域 D329A 点突变的小鼠模型。该突变导致出生后生长迟缓的显性遗传。在分子水平上，它导致 H3K27me3 和双价染色质标记的结构域中 DNA 过度甲基化，以及成年下丘脑发育调节基因的去抑制。对非 CpG 甲基化（一种新甲基化的标志物）的评估进一步证明了 DNMT3A 在双价结构域中的募集和活性改变。这项工作为 DNMT3A-PWWP 结构域的功能以及 DNMT3A 在调节出生后生长中的作用提供了关键的分子见解。
