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.

中文翻译：

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通过COMPASS，Polycomb和DNA甲基化的平衡，将组蛋白H3K4三甲基化与发育基因表达脱钩。

COMPASS蛋白家族可催化组蛋白H3 Lys 4（H3K4）甲基化，其成员对于调节基因表达至关重要。MLL2 / COMPASS使许多发育基因和二价簇上的H3K4甲基化。为了了解MLL2依赖的转录调控，我们进行了基于CRISPR的筛选，将MLL2依赖的基因作为小鼠胚胎干细胞中的报告基因。我们发现MLL2通过排斥PRC2和DNA甲基化机制来保护发育基因免受阻抑，从而在基因表达中发挥作用。因此，通过抑制PRC2和DNA甲基转移酶可以减轻在没有MLL2的情况下的抑制。此外，此类基因座上的DNA去甲基化不仅通过去除DNA甲基化，而且通过开放先前的CpG甲基化区域进行PRC2募集，都可以重新激活MLL2依赖性基因，在Polycomb抑制的基因上稀释PRC2。这些发现揭示了染色质的这三种表观遗传修饰子的背景和功能如何协调转录决定，并证明了通过酶而不是H3K4三甲基化来预防主动抑制是MLL2 / COMPASS靶标转录调控的基础。