A role of Polycomb in the maintenance of hypomethylation for DNA methylation valley

DNA methylation valleys (DMVs) are large loci that are devoid of DNA methylation in the genome. We show that DMVs are hypomethylated at most stages in development and are highly conserved across vertebrates. Importantly, DMVs are hotspots of regulatory regions for key developmental regulator genes. 4C-seq analyses indicate that DMVs are insulated and self-interacting domains. By analyzing a panel of DNA methylomes for the mouse tissues, we have identified a subset of DMVs that are dynamically methylated. These DMVs are strongly enriched by Polycomb and their histone substrate H3K27me3 when the associated genes are silenced, and surprisingly show elevated DNA methylation upon gene activation. In support of a role of Polycomb in DMV hypomethylation, we observed aberrant methylation in DMVs in mESCs deficient for Eed. Finally, we showed that Polycomb regulates hypomethylation of DMVs likely through TET proteins. Overall design: Through a global survey DMVs in different species and different developmental stages , we validated DMVs play important role in gene regulation and development. Further studying different types of DMVs in vivo, Polycomb-target DMVs are more enriched TFs. Next, we continue to finding out what roles Polycomb plays in maintenance hypomethylation of DMVs and how it regulates DNA methylation in DMVs.DNA甲基化谷（DNA methylation valleys, DMVs）是基因组中缺乏DNA甲基化的大型基因座。本研究证实，DMVs在多数发育阶段均处于低甲基化状态，且在脊椎动物中高度保守。值得注意的是，DMVs是关键发育调控基因的调控区域热点。4C测序（4C-seq）分析显示，DMVs属于绝缘且自身相互作用的结构域。通过分析小鼠组织的多组DNA甲基化组，本研究鉴定出一类动态甲基化的DMVs亚群。当关联基因处于沉默状态时，这类DMVs会被多梳蛋白（Polycomb）及其组蛋白底物H3K27me3显著富集；而令人意外的是，在基因激活时，DMVs的DNA甲基化水平反而升高。为证实多梳蛋白在DMV低甲基化中的作用，本研究在Eed基因缺陷的小鼠胚胎干细胞（mESCs）的DMVs中观察到了异常甲基化现象。最后，本研究证实，多梳蛋白大概率通过TET蛋白调控DMVs的低甲基化状态。研究设计概述：通过对不同物种、不同发育阶段的DMVs开展全局分析，本研究验证了DMVs在基因调控与发育过程中发挥重要作用。进一步的体内研究显示，靶向多梳蛋白的DMVs更易富集转录因子（TFs）。后续本研究将继续阐明多梳蛋白在维持DMV低甲基化状态中所扮演的角色，以及其调控DMVs DNA甲基化的具体机制。