当前位置:科学网首页 > 小柯机器人 >详情
研究揭示基因间甲基化调控机制
作者:小柯机器人 发布时间:2019/9/5 13:59:51

美国哥伦比亚大学Chao Lu、加拿大麦吉尔大学Jacek Majewski和美国洛克菲勒大学C. David Allis等课题组合作,发现被H3K36me2标记的组蛋白招募DNA甲基转移酶3A(DNMT3A),并塑造基因间DNA甲基化图谱。相关论文2019年9月4日在线发表在《自然》上。

据了解, 催化DNA中CpG岛的甲基化的酶,包括 DNMT1,DNMT3A和DNMT3B,对于哺乳动物组织发育和体内稳态是必不可少的。它们还涉及人类发育障碍和癌症,支持DNA甲基化在细胞命运特化和维持中起关键作用。以前的研究表明,组蛋白的翻译后修饰涉及指定启动子和活跃转录基因体的DNA甲基转移酶定位和DNA甲基化的模式。然而,调控基因间DNA甲基化的建立和维持的机制仍然知之甚少。Tatton-Brown-Rahman综合征(TBRS)是一种儿童过度生长障碍,由DNMT3A中的种系突变造成的。TBRS与Sotos综合征(由NSD1的单倍不足引起的,NSD1是一种组蛋白甲基转移酶,催化组蛋白H3在K36(H3K36me2)的二甲基化),这表明这两种疾病之间存在机制联系。

研究报道了NSD1介导的H3K36me2,是基因间区域DNMT3A的募集和DNA甲基化维持所必需的。全基因组分析显示,DNMT3A的结合和活性,与常染色质的非编码区域的H3K36me2共定位。在小鼠细胞中遗传敲除Nsd1及其旁系同源物Nsd2,导致DNMT3A重新分布至H3K36me3修饰的基因体,并且减少基因间DNA的甲基化。来自患有Sotos综合征和NSD1突变体肿瘤的患者的血液样品,也表现出基因间DNA的低甲基化。DNMT3A的PWWP结构域在体外显示H3K36me2和H3K36me3的双重识别,对H3K36me2具有更高的结合亲和力,H3K36me2会被TBRS衍生的错义突变消除。总之,研究揭示了一种跨染色质调节途径,它将异常的基因间CpG岛甲基化与人类肿瘤和发育过度生长联系起来。

附:英文原文

Title: The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape

Author: Daniel N. Weinberg, Simon Papillon-Cavanagh, Haifen Chen, Yuan Yue, Xiao Chen, Kartik N. Rajagopalan, Cynthia Horth, John T. McGuire, Xinjing Xu, Hamid Nikbakht, Agata E. Lemiesz, Dylan M. Marchione, Matthew R. Marunde, Matthew J. Meiners, Marcus A. Cheek, Michael-Christopher Keogh, Eric Bareke, Anissa Djedid, Ashot S. Harutyunyan, Nada Jabado, Benjamin A. Garcia, Haitao Li, C. David Allis, Jacek Majewski, Chao Lu

Issue&Volume: 2019-09-04

Abstract: Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis14. They are also implicated in human developmental disorders and cancers58, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies911. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. TattonBrownRahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in DNMT3A. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of NSD1, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)8,12,13), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of Nsd1 and its paralogue Nsd2 in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and NSD1-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a trans-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.

DOI: 10.1038/s41586-019-1534-3

Source:https://www.nature.com/articles/s41586-019-1534-3

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html