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The Elongation Factor Spt6 Maintains ESC Pluripotency by Controlling Super-Enhancers and Counteracting Polycomb Proteins
Molecular Cell ( IF 14.5 ) Pub Date : 2017-10-12 , DOI: 10.1016/j.molcel.2017.09.016
A. Hongjun Wang , Aster H. Juan , Kyung Dae Ko , Pei-Fang Tsai , Hossein Zare , Stefania Dell’Orso , Vittorio Sartorelli

Spt6 coordinates nucleosome dis- and re-assembly, transcriptional elongation, and mRNA processing. Here, we report that depleting Spt6 in embryonic stem cells (ESCs) reduced expression of pluripotency factors, increased expression of cell-lineage-affiliated developmental regulators, and induced cell morphological and biochemical changes indicative of ESC differentiation. Selective downregulation of pluripotency factors upon Spt6 depletion may be mechanistically explained by its enrichment at ESC super-enhancers, where Spt6 controls histone H3K27 acetylation and methylation and super-enhancer RNA transcription. In ESCs, Spt6 interacted with the PRC2 core subunit Suz12 and prevented H3K27me3 accumulation at ESC super-enhancers and associated promoters. Biochemical as well as functional experiments revealed that Spt6 could compete for binding of the PRC2 methyltransferase Ezh2 to Suz12 and reduce PRC2 chromatin engagement. Thus, in addition to serving as a histone chaperone and transcription elongation factor, Spt6 counteracts repression by opposing H3K27me3 deposition at critical genomic regulatory regions.



中文翻译:

延伸因子Spt6通过控制超级增强剂和抵消多梳蛋白来维持ESC多能性。

Spt6协调核小体的拆卸和重组,转录延伸和mRNA加工。在这里,我们报告在胚胎干细胞(ESCs)中减少Spt6减少了多能性因子的表达,增加了细胞谱系相关的发育调节剂的表达,并诱导了指示ESC分化的细胞形态和生化变化。Spt6耗尽后多能性因子的选择性下调可能是通过其在ESC超级增强子中的富集来进行机械解释的,其中Spt6控制组蛋白H3K27乙酰化和甲基化以及超级增强子RNA转录。在电调中,Spt6与PRC2核心亚基Suz12相互作用,并阻止H3K27me3在电调超级增强子和相关启动子处积聚。生化和功能实验表明,Spt6可以竞争PRC2甲基转移酶Ezh2与Suz12的结合并减少PRC2染色质的结合。因此,除了用作组蛋白分子伴侣和转录延伸因子外,Spt6还通过在重要的基因组调控区阻止H3K27me3沉积来抵消抑制作用。

更新日期:2017-10-12
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