Not All H3K4 Methylations Are Created Equal: Mll2/COMPASS Dependency in Primordial Germ Cell Specification.
Not All H3K4 Methylations Are Created Equal: Mll2/COMPASS Dependency in Primordial Germ Cell Specification.
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DOI：
10.1016/j.molcel.2017.01.013
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发表时间：
2017-02-02
期刊：
影响因子：
16
通讯作者：
Shilatifard A
中科院分区：
文献类型：
--
作者：
Hu D;Gao X;Cao K;Morgan MA;Mas G;Smith ER;Volk AG;Bartom ET;Crispino JD;Di Croce L;Shilatifard A
基因表达的时空调控是胚胎发育过程中细胞系规范的核心，是通过转录因子/辅助因子和顺式调控元件的表观遗传状态的组合作用来实现的。之前，我们报道了Mll2 (KMT2B)/COMPASS负责在二价基因的启动子上实现H3K4me3。在这里，我们发现Mll2/COMPASS也可以在一些非tss调控元件上实现H3K4me3，其中一部分具有活性增强子的表观遗传特征。我们的机制研究表明，Mll2的CXXC结构域与富含cpg的区域的关联在染色质靶向和H3K4me3的后续实施中起着重要作用。尽管Mll2/COMPASS对于H3K4me3在数千个位点的实现是必需的，但它似乎对于一部分基因的表达是必不可少的，包括那些在胚胎发育过程中控制转录程序的基因，这表明并非所有由Mll2/COMPASS实现的H3K4三甲基化在功能上都是相同的。Hu等人分析了MLL2的甲基转移酶和CXXC结构域在小鼠ES细胞H3K4三甲基化中的作用，发现虽然MLL2在二价基因启动子和非tss元件上都使H3K4三甲基化，但它只调节有限数量基因的转录，包括PGC规范所需的基因。
The spatiotemporal regulation of gene expression is central for cell-lineage specification during embryonic development and is achieved through the combinatorial action of transcription factors/co-factors and the epigenetic states at cis-regulatory elements. Previously, we reported that Mll2 (KMT2B)/COMPASS is responsible for the implementation of H3K4me3 at promoters of bivalent genes. Here, we show that Mll2/COMPASS can also implements H3K4me3 at some of the non-TSS regulatory elements, a subset of which share epigenetic signatures of active enhancers. Our mechanistic studies reveal that the association of Mll2’s CXXC domain with CpG-rich regions plays an instrumental role for chromatin targeting and subsequent implementation of H3K4me3. Although Mll2/COMPASS is required for H3K4me3 implementation on thousands of sites, it appears to be essential for the expression of a subset of genes, including those functioning in the control of transcriptional programs during embryonic development, indicating that not all H3K4 trimethylations implemented by MLL2/COMPASS are functionally equivalent. Hu et al. analyzed the contribution of MLL2’s methyltransferase and CXXC domain in the trimethylation of H3K4 in mouse ES cells and find that while it trimethylates H3K4 at both bivalent gene promoters and non-TSS elements, it regulates transcription at a limited number of genes including those required for PGC specification.