Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes.
Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes.
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DOI：
10.1016/j.celrep.2014.08.055
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发表时间：
2014-10-09
期刊：
影响因子：
8.8
通讯作者：
Hernando E
中科院分区：
文献类型：
--
作者：
Di Micco R;Fontanals-Cirera B;Low V;Ntziachristos P;Yuen SK;Lovell CD;Dolgalev I;Yonekubo Y;Zhang G;Rusinova E;Gerona-Navarro G;Cañamero M;Ohlmeyer M;Aifantis I;Zhou MM;Tsirigos A;Hernando E
转录因子和染色质重塑复合体是胚胎干细胞(ESC)特性的关键决定因素。在这里，我们证明了BRD4是表观遗传阅读器的溴域和端外域(BET)家族的成员，它调节ESCs的自我更新能力和多能性。BRD4抑制导致上皮-间充质转化(EMT)标志物的诱导和对神经外胚层谱系的承诺，同时降低了畸胎瘤的ESC多分化能力。BRD4通过占据OCT4和PRDM14等核心干细胞基因的超级增强子(SE)和大簇调节元件，并向它们招募Mediator和CDK9(正转录延伸因子b(P-TEFb)的催化亚基)来维持核心干细胞基因的转录，从而允许Pol-II依赖的生产性延长。我们的研究描述了一种调节ESC同一性的机制，可以应用于提高ESC分化的效率。
Transcription factors and chromatin-remodeling complexes are key determinants of embryonic stem cell (ESC) identity. Here, we demonstrate that BRD4, a member of the bromodomain and extraterminal domain (BET) family of epigenetic readers, regulates the self-renewal ability and pluripotency of ESCs. BRD4 inhibition resulted in induction of epithelial-tomesenchymal transition (EMT) markers and commitment to the neuroectodermal lineage while reducing the ESC multidifferentiation capacity in teratoma as-says. BRD4 maintains transcription of core stem cell genes such as OCT4 and PRDM14 by occupying their super-enhancers (SEs), large clusters of regulatory elements, and recruiting to them Mediator and CDK9, the catalytic subunit of the positive transcription elongation factor b (P-TEFb), to allow Pol-II-dependent productive elongation. Our study describes a mechanism of regulation of ESC identity that could be applied to improve the efficiency of ESC differentiation.
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