Mll2 is required for H3K4 trimethylation on bivalent promoters in embryonic stem cells, whereas Mll1 is redundant
Mll2 is required for H3K4 trimethylation on bivalent promoters in embryonic stem cells, whereas Mll1 is redundant
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DOI：
10.1242/dev.102681
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发表时间：
2014-02-01
期刊：
影响因子：
4.6
通讯作者：
Stewart, A. Francis
中科院分区：
文献类型：
--
作者：
Denissov, Sergei;Hofemeister, Helmut;Stewart, A. Francis
组蛋白H3赖氨酸4（H3 K4 me 3）的三甲基化是一种普遍的表观遗传标记，也是三胸组作用的关键产物。在这里，我们表明，Mll 2，六个Set 1/Trithorax型H3 K4甲基转移酶在哺乳动物中的一个，是需要在小鼠胚胎干细胞的二价启动子的三甲基化。M112与二价启动子结合，但也与大多数活性启动子结合，其不需要M112用于H3 K4 me 3或mRNA表达。相比之下，Set 1复合物（Set 1C）亚基Cxxc 1主要与活性启动子结合，但不与二价启动子结合。这表明二价启动子依赖于M112的H3 K4 me 3，而活性启动子具有多于一个结合的H3 K4甲基转移酶，包括Set 1C。去除Mll 2的姐妹Mll 1对任何启动子几乎没有影响，除非也去除Mll 2，表明这些酶之间的功能备份。除了一个子集，损失的H3 K4 me 3的二价启动子并没有阻止响应视黄酸，从而反对引发模型的二价。相比之下，我们建议，MLL 2是先驱三甲基转移酶启动子定义在幼稚表观基因组和Polycomb组的行动，二价启动子阻止过早建立活跃的，Set 1C结合，启动子。
Trimethylation of histone H3 lysine 4 (H3K4me3) at the promoters of actively transcribed genes is a universal epigenetic mark and a key product of Trithorax group action. Here, we show that Mll2, one of the six Set1/Trithorax-type H3K4 methyltransferases in mammals, is required for trimethylation of bivalent promoters in mouse embryonic stem cells. Mll2 is bound to bivalent promoters but also to most active promoters, which do not require Mll2 for H3K4me3 or mRNA expression. By contrast, the Set1 complex (Set1C) subunit Cxxc1 is primarily bound to active but not bivalent promoters. This indicates that bivalent promoters rely on Mll2 for H3K4me3 whereas active promoters have more than one bound H3K4 methyltransferase, including Set1C. Removal of Mll1, sister to Mll2, had almost no effect on any promoter unless Mll2 was also removed, indicating functional backup between these enzymes. Except for a subset, loss of H3K4me3 on bivalent promoters did not prevent responsiveness to retinoic acid, thereby arguing against a priming model for bivalency. In contrast, we propose that Mll2 is the pioneer trimethyltransferase for promoter definition in the naive epigenome and that Polycomb group action on bivalent promoters blocks the premature establishment of active, Set1C-bound, promoters.