美国洛克菲勒大学C. David Allis和加拿大麦吉尔大学Jacek Majewski研究组合作取得最新进展。他们发现DNMT3A募集的两种竞争机制调节了以Polycomb阻抑复合物1（PRC1）为靶标的CpG岛的从头DNA甲基化的动力学。该项研究成果发表在2021年5月13日出版的《自然-遗传学》杂志上。

他们报告，DNMT3A PWWP结构域突变在神经节瘤和小头畸形中鉴定出，以PRC1依赖性方式促进DNMT3A异常定位到CpG岛（CGI）。DNMT3A PWWP突变体积聚在包含PRC1介导的单泛素化组蛋白H2A赖氨酸119（H2AK119ub）形成的区域，而不涉及PRC2催化的三甲基化组蛋白H3赖氨酸27（H3K27me3）的形成量。DNMT3A通过假定的氨基末端泛素依赖性募集区与H2AK119ub修饰的核小体相互作用，从而提供了DNMT3A基因组靶向的另一种形式，这种形式因PWWP阅读器功能的丧失而增强。PRC1的消融消除了DNMT3A PWWP突变体对CGI的定位，并防止了异常的DNA超甲基化。他们的研究表明，通过不同的阅读器结构域募集DNMT3A之间的平衡指导了从头CpG甲基化，并且可能是在某些人类癌症亚型和发育障碍中观察到的异常DNA甲基化态势的基础。

据了解，CpG甲基化的精确沉积对于哺乳动物的发育和组织稳态至关重要，而且在人类疾病中常常失调。从头DNA甲基转移酶DNMT3A的定位通过其PWWP域识别组蛋白H3赖氨酸36（H3K36）甲基化而得以促进，并且通常在CGI处被耗尽。然而，也已经观察到由PRC调节的CGI的甲基化。

附：英文原文

Title: Two competing mechanisms of DNMT3A recruitment regulate the dynamics of de novo DNA methylation at PRC1-targeted CpG islands

Author: Daniel N. Weinberg, Phillip Rosenbaum, Xiao Chen, Douglas Barrows, Cynthia Horth, Matthew R. Marunde, Irina K. Popova, Zachary B. Gillespie, Michael-Christopher Keogh, Chao Lu, Jacek Majewski, C. David Allis

Issue&Volume: 2021-05-13

Abstract: Precise deposition of CpG methylation is critical for mammalian development and tissue homeostasis and is often dysregulated in human diseases. The localization of de novo DNA methyltransferase DNMT3A is facilitated by its PWWP domain recognizing histone H3 lysine 36 (H3K36) methylation1,2 and is normally depleted at CpG islands (CGIs)3. However, methylation of CGIs regulated by Polycomb repressive complexes (PRCs) has also been observed4,5,6,7,8. Here, we report that DNMT3A PWWP domain mutations identified in paragangliomas9 and microcephalic dwarfism10 promote aberrant localization of DNMT3A to CGIs in a PRC1-dependent manner. DNMT3A PWWP mutants accumulate at regions containing PRC1-mediated formation of monoubiquitylated histone H2A lysine 119 (H2AK119ub), irrespective of the amounts of PRC2-catalyzed formation of trimethylated histone H3 lysine 27 (H3K27me3). DNMT3A interacts with H2AK119ub-modified nucleosomes through a putative amino-terminal ubiquitin-dependent recruitment region, providing an alternative form of DNMT3A genomic targeting that is augmented by the loss of PWWP reader function. Ablation of PRC1 abrogates localization of DNMT3A PWWP mutants to CGIs and prevents aberrant DNA hypermethylation. Our study implies that a balance between DNMT3A recruitment by distinct reader domains guides de novo CpG methylation and may underlie the abnormal DNA methylation landscapes observed in select human cancer subtypes and developmental disorders.

DOI: 10.1038/s41588-021-00856-5

Source: https://www.nature.com/articles/s41588-021-00856-5