Epigenetic modifications on the chromatin do not occur in isolation. Chromatin-associated proteins and their modification products form a highly interconnected network, and disturbing one component may rearrange the entire system. We see this increasingly clearly in epigenetically dysregulated cancers. It is important to understand the rules governing epigenetic interactions. Here, we use the mouse embryonic stem cell (mESC) model to describe in detail the relationships within the H3K27-H3K36-DNA methylation subnetwork. In particular, we focus on the major epigenetic reorganization caused by deletion of the histone 3 lysine 36 methyltransferase NSD1, which in mESCs deposits nearly all of the intergenic H3K36me2. Although disturbing the H3K27 and DNA methylation (DNAme) components also affects this network to a certain extent, the removal of H3K36me2 has the most drastic effect on the epigenetic landscape, resulting in full intergenic spread of H3K27me3 and a substantial decrease in DNAme. By profiling DNMT3A and CHH methylation (mCHH), we show that H3K36me2 loss upon Nsd1-KO leads to a massive redistribution of DNMT3A and mCHH away from intergenic regions and toward active gene bodies, suggesting that DNAme reduction is at least in part caused by redistribution of de novo methylation. Additionally, we show that pervasive acetylation of H3K27 is regulated by the interplay of H3K36 and H3K27 methylation. Our analysis highlights the importance of H3K36me2 as a major determinant of the developmental epigenome and provides a framework for further consolidating our knowledge of epigenetic networks.

中文翻译：

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H3K36 二甲基化通过指导胚胎干细胞中的抑制性染色质修饰来塑造表观遗传相互作用景观

染色质的表观遗传修饰并不是孤立发生的。染色质相关蛋白及其修饰产物形成一个高度互连的网络，干扰一个组件可能会重新排列整个系统。我们在表观遗传失调的癌症中越来越清楚地看到这一点。了解表观遗传相互作用的规则很重要。在这里，我们使用小鼠胚胎干细胞 (mESC) 模型来详细描述 H3K27-H3K36-DNA 甲基化子网络内的关系。我们特别关注组蛋白 3 赖氨酸 36 甲基转移酶 NSD1 缺失引起的主要表观遗传重组，该酶在 mESC 中沉积了几乎所有基因间 H3K36me2。虽然扰乱H3K27和DNA甲基化（DNAme）成分也会在一定程度上影响这个网络，H3K36me2 的去除对表观遗传景观具有最剧烈的影响，导致 H3K27me3 的完全基因间扩散和 DNAme 的大幅减少。通过分析 DNMT3A 和 CHH 甲基化 (mCHH)，我们表明 H3K36me2 丢失Nsd1 -KO导致DNMT3A和mCHH从基因间区域向活性基因体大规模重新分布，表明DNAme减少至少部分是由从头甲基化的重新分布引起的。此外，我们发现 H3K27 的普遍乙酰化受到 H3K36 和 H3K27 甲基化相互作用的调节。我们的分析强调了 H3K36me2 作为发育表观基因组主要决定因素的重要性，并为进一步巩固我们对表观遗传网络的知识提供了一个框架。