H2A.Z facilitates access of active and repressive complexes to chromatin in embryonic stem cell self-renewal and differentiation.
H2A.Z facilitates access of active and repressive complexes to chromatin in embryonic stem cell self-renewal and differentiation.
复制标题
H2A.Z 在胚胎干细胞自我更新和分化过程中促进活性复合物和抑制复合物接触染色质。
DOI：
10.1016/j.stem.2012.11.003
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发表时间：
2013-02-07
期刊：
影响因子：
23.9
通讯作者：
Zhao K
中科院分区：
文献类型：
--
作者：
Hu G;Cui K;Northrup D;Liu C;Wang C;Tang Q;Ge K;Levens D;Crane-Robinson C;Zhao K
染色质修饰与胚胎干细胞(ESCs)的自我更新和分化有关。然而，组蛋白变异体H_2A.Z在胚胎干细胞中的功能仍不清楚。我们发现H_2A.Z在启动子和增强子上高度丰富，是小鼠胚胎干细胞高效自我更新和分化所必需的。H2A.Z沉积导致核小体结构异常，核小体占有率降低，染色质可及性增加。在自我更新的ESCs中，H2A.Z的敲除影响了OCT4与其靶基因的结合，并导致MLL复合体与活性基因的结合减少，PRC2复合体与抑制基因的结合减少。在胚胎干细胞分化过程中，抑制H_2A.Z还可抑制RA诱导的RARα结合、分化标志物的激活和多能性基因的抑制。我们认为，H_2A.Z通过充当“一般促进者”，为激活和抑制的各种复合体产生通路，从而调节这种相反的活动。
Chromatin modifications have been implicated in the self-renewal and differentiation of embryonic stem cells (ESCs). However, the function of histone variant H2A.Z in ESCs remains unclear. We show that H2A.Z is highly enriched at promoters and enhancers and is required for both efficient self-renewal and differentiation of murine ESCs. H2A.Z deposition leads to an abnormal nucleosome structure, decreased nucleosome occupancy and increased chromatin accessibility. In self-renewing ESCs, knockdown of H2A.Z compromises OCT4 binding to its target genes and leads to decreased binding of MLL complexes to active genes and of PRC2 complex to repressed genes. During differentiation of ESCs, inhibition of H2A.Z also compromises RA-induced RARα binding, activation of differentiation markers and the repression of pluripotency genes. We propose that H2A.Z mediates such contrasting activities by acting as a ‘general facilitator’ that generates access for a variety of complexes both activating and repressive.