MeCP2 Represses Enhancers through Chromosome Topology-Associated DNA Methylation.,Molecular Cell

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MeCP2 Represses Enhancers through Chromosome Topology-Associated DNA Methylation.
Molecular Cell ( IF 14.5 ) Pub Date : 2019-11-26 , DOI: 10.1016/j.molcel.2019.10.033
Adam W Clemens ₁ , Dennis Y Wu ₁ , J Russell Moore ₁ , Diana L Christian ₁ , Guoyan Zhao ₁ , Harrison W Gabel ₁

Affiliation

The genomes of mammalian neurons contain uniquely high levels of non-CG DNA methylation that can be bound by the Rett syndrome protein, MeCP2, to regulate gene expression. How patterns of non-CG methylation are established in neurons and the mechanism by which this methylation works with MeCP2 to control gene expression is unclear. Here, we find that genes repressed by MeCP2 are often located within megabase-scale regions of high non-CG methylation that correspond with topologically associating domains of chromatin folding. MeCP2 represses enhancers found in these domains that are enriched for non-CG and CG methylation, with the strongest repression occurring for enhancers located within MeCP2-repressed genes. These alterations in enhancer activity provide a mechanism for how MeCP2 disruption in disease can lead to widespread changes in gene expression. Hence, we find that DNA topology can shape non-CG DNA methylation across the genome to dictate MeCP2-mediated enhancer regulation in the brain.

中文翻译：

MeCP2 通过染色体拓扑相关的 DNA 甲基化抑制增强子。

哺乳动物神经元的基因组含有独特的高水平非 CG DNA 甲基化，可以与 Rett 综合征蛋白 MeCP2 结合来调节基因表达。非 CG 甲基化模式是如何在神经元中建立的，以及这种甲基化与 MeCP2 一起控制基因表达的机制尚不清楚。在这里，我们发现被 MeCP2 抑制的基因通常位于高非 CG 甲基化的兆碱基级区域内，该区域与染色质折叠的拓扑关联域相对应。 MeCP2 抑制在这些富含非 CG 和 CG 甲基化的结构域中发现的增强子，其中最强的抑制发生在位于 MeCP2 抑制基因内的增强子。这些增强子活性的改变为疾病中 MeCP2 的破坏如何导致基因表达的广泛变化提供了一种机制。因此，我们发现 DNA 拓扑结构可以塑造整个基因组的非 CG DNA 甲基化，从而决定大脑中 MeCP2 介导的增强子调节。

更新日期：2019-11-27

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