Regulation of Promoter and Enhancer Histone Landscape by DNA Methylation in Embryonic Stem Cells (RRBS)

In this study, we mapped modification of lysine 4 and lysine 27 of histone H3 genome-wide in a series of mouse embryonic stem cells (mESCs) varying in DNA methylation levels based on knock-out and reconstitution of DNA methyltransferases (DNMTs). We extend previous studies showing cross-talk between DNA methylation and histone modifications by examining a breadth of histone modifications, causal relationships, and direct effects. Our data shows a causal regulation of H3K27me3 at gene promoters as well as H3K27ac and H3K27me3 at tissue-specific enhancers. We also identify isoform differences between DNMT family members. This study provides a comprehensive resource for the study of the complex interplay between DNA methylation and histone modification landscape.

本研究通过敲除与重构DNA甲基转移酶（DNMTs），构建了一系列DNA甲基化水平存在差异的小鼠胚胎干细胞（mESCs）模型，并在此模型中对组蛋白H3的赖氨酸4（H3K4）与赖氨酸27（H3K27）位点的修饰进行了全基因组图谱绘制。本研究通过分析多种组蛋白修饰类型、因果关联与直接调控效应，拓展了此前关于DNA甲基化与组蛋白修饰之间串扰的研究成果。本研究数据揭示了基因启动子区域H3K27me3的因果调控关系，以及组织特异性增强子区域H3K27ac与H3K27me3的因果调控关系。本研究还鉴定出了DNMT家族成员间的剪接变体差异。本研究为解析DNA甲基化与组蛋白修饰图谱间的复杂相互作用提供了全面的研究资源。