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通过 COMPASS、Polycomb 和 DNA 甲基化之间的平衡，将组蛋白 H3K4 三甲基化与发育基因表达解偶联。

Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation.

机构信息

Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

出版信息

Nat Genet. 2020 Jun;52(6):615-625. doi: 10.1038/s41588-020-0618-1. Epub 2020 May 11.

DOI:10.1038/s41588-020-0618-1
PMID:32393859
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7790509/
Abstract

The COMPASS protein family catalyzes histone H3 Lys 4 (H3K4) methylation and its members are essential for regulating gene expression. MLL2/COMPASS methylates H3K4 on many developmental genes and bivalent clusters. To understand MLL2-dependent transcriptional regulation, we performed a CRISPR-based screen with an MLL2-dependent gene as a reporter in mouse embryonic stem cells. We found that MLL2 functions in gene expression by protecting developmental genes from repression via repelling PRC2 and DNA methylation machineries. Accordingly, repression in the absence of MLL2 is relieved by inhibition of PRC2 and DNA methyltransferases. Furthermore, DNA demethylation on such loci leads to reactivation of MLL2-dependent genes not only by removing DNA methylation but also by opening up previously CpG methylated regions for PRC2 recruitment, diluting PRC2 at Polycomb-repressed genes. These findings reveal how the context and function of these three epigenetic modifiers of chromatin can orchestrate transcriptional decisions and demonstrate that prevention of active repression by the context of the enzyme and not H3K4 trimethylation underlies transcriptional regulation on MLL2/COMPASS targets.

摘要

COMPASS 蛋白家族催化组蛋白 H3 赖氨酸 4（H3K4）甲基化，其成员对于调节基因表达至关重要。MLL2/COMPASS 在许多发育基因和双价簇上甲基化 H3K4。为了理解 MLL2 依赖性转录调控，我们在小鼠胚胎干细胞中进行了基于 CRISPR 的筛选，以 MLL2 依赖性基因为报告基因。我们发现，MLL2 通过排斥 PRC2 和 DNA 甲基化酶来保护发育基因免受抑制，从而在基因表达中发挥作用。因此，在没有 MLL2 的情况下，通过抑制 PRC2 和 DNA 甲基转移酶可以缓解抑制。此外，这些位点上的 DNA 去甲基化不仅通过去除 DNA 甲基化，而且通过打开先前 CpG 甲基化的区域以招募 PRC2，从而使 PRC2 在多梳抑制基因上稀释，导致 MLL2 依赖性基因的重新激活。这些发现揭示了这三种染色质表观遗传修饰剂的上下文和功能如何协调转录决策，并表明酶的上下文而不是 H3K4 三甲基化防止活性抑制是 MLL2/COMPASS 靶标转录调控的基础。

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