Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Stem Cell. 2013 Feb 7;12(2):180-92. doi: 10.1016/j.stem.2012.11.003. Epub 2012 Dec 20.
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.
染色质修饰与胚胎干细胞（ESCs）的自我更新和分化有关。然而，组蛋白变体 H2A.Z 在 ESCs 中的功能仍不清楚。我们发现 H2A.Z 在启动子和增强子上高度富集，并且对于小鼠 ESCs 的有效自我更新和分化都是必需的。H2A.Z 的沉积导致异常核小体结构、核小体占有率降低和染色质可及性增加。在自我更新的 ESCs 中，H2A.Z 的敲低会损害 OCT4 与其靶基因的结合，导致 MLL 复合物与活性基因的结合减少，PRC2 复合物与抑制基因的结合减少。在 ESCs 的分化过程中，H2A.Z 的抑制也会损害 RA 诱导的 RARα 结合、分化标记的激活以及多能性基因的抑制。我们提出，H2A.Z 通过作为一个通用的促进因子来发挥作用，为各种激活和抑制复合物提供了进入的机会，从而介导了这种相反的活性。
