Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation.
Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation.
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DOI：
10.1038/s41588-020-0618-1
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发表时间：
2020-06
期刊：
影响因子：
30.8
通讯作者：
Shilatifard A
中科院分区：
文献类型：
--
作者：
Douillet D;Sze CC;Ryan C;Piunti A;Shah AP;Ugarenko M;Marshall SA;Rendleman EJ;Zha D;Helmin KA;Zhao Z;Cao K;Morgan MA;Singer BD;Bartom ET;Smith ER;Shilatifard A
COMPASS蛋白家族催化组蛋白H3赖氨酸4(H3K4)甲基化，其成员是调控基因表达的重要成员。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，我们在小鼠胚胎干细胞(MESCs)中进行了以MLL2依赖基因为报告的CRISPR筛选，发现MLL2通过排斥PRC2和DNA甲基化机制保护发育基因免受抑制而在基因表达中发挥作用。因此，在缺乏MLL2的情况下，通过抑制PRC2和DNA甲基转移酶来缓解抑制。此外，在这些基因座上招募DNA去甲基化机制不仅通过消除DNA甲基化，而且通过打开先前的CpG甲基化区域来招募PrC2，稀释多聚梳抑制基因上的PrC2，导致依赖于mll2的基因重新激活。这些发现揭示了染色质的这三个表观遗传修饰物的背景和功能是如何协调转录决定的，并证明了通过酶的背景而不是H3K4me3来防止主动抑制是基于对MLL2/COMPASS靶标的转录调控。
The COMPASS protein family catalyzes histone H3 lysine 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 (mESCs) and 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, recruitment of DNA demethylation machineries 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 H3K4me3 underlies transcriptional regulation on MLL2/COMPASS targets.
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影响因子：
16.8
作者：
Hu D;Garruss AS;Gao X;Morgan MA;Cook M;Smith ER;Shilatifard A
通讯作者：
Shilatifard A
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
12.3
作者：
Li Z;Dai H;Martos SN;Xu B;Gao Y;Li T;Zhu G;Schones DE;Wang Z
通讯作者：
Wang Z
影响因子：
4.8
作者：
Lee, JH;Skalnik, DG
通讯作者：
Skalnik, DG
影响因子：
10.5
作者：
Clouaire, Thomas;Webb, Shaun;Bird, Adrian
通讯作者：
Bird, Adrian