Burke Medical Research Institute, White Plains, NY 10605, USA; Department of Neuroscience, Brain Mind Research Institute, Department of Cell & Development, Weill Cornell Medical College, New York, NY 10065, USA.
Burke Medical Research Institute, White Plains, NY 10605, USA; Department of Neuroscience, Brain Mind Research Institute, Department of Cell & Development, Weill Cornell Medical College, New York, NY 10065, USA.
Cell Rep. 2018 Nov 13;25(7):1756-1771. doi: 10.1016/j.celrep.2018.10.003.
The pluripotent state of embryonic stem cells (ESCs) is defined by its transcriptome and epigenome. The chromatin reader Brd4 determines ESC identity. Although Brd4 regulation in gene transcription has been well described, its contribution to the chromatin landscape is less known. Here, we show that Brd4's bromodomains partner with the histone acetyltransferase P300, increasing its enzymatic activities. Augmenting histone acetylation by Brd4-P300 interaction recruits the chromatin remodeler Brg1 altering chromatin structure. This pathway is important for maintaining the expression and chromatin patterns of pluripotency-associated genes, such as Oct4, Nanog, and the X chromosome regulatory long noncoding RNAs Tsix and Xite. Furthermore, we show that the Brd4-P300 interaction regulates the de novo formation of chromatin marks during ESC differentiation, as exemplified by controlling the master regulators of mesoderm formation. Collectively, we delineate the function of Brd4 in organizing the chromatin structure that contributes to gene transcriptional regulation and cell fate determination.
胚胎干细胞（ESCs）的多能状态由其转录组和表观基因组定义。染色质阅读器 Brd4 决定 ESC 身份。虽然 Brd4 在基因转录中的调控已经得到很好的描述，但它对染色质景观的贡献知之甚少。在这里，我们表明 Brd4 的溴结构域与组蛋白乙酰转移酶 P300 结合，增加其酶活性。Brd4-P300 相互作用通过招募染色质重塑酶 Brg1 增加组蛋白乙酰化，从而改变染色质结构。该途径对于维持多能性相关基因（如 Oct4、Nanog 和 X 染色体调节长非编码 RNA Tsix 和 Xite）的表达和染色质模式至关重要。此外，我们还表明，Brd4-P300 相互作用在 ESC 分化过程中调节染色质标记的从头形成，例如控制中胚层形成的主调节因子。总之，我们描绘了 Brd4 在组织染色质结构中的功能，该结构有助于基因转录调控和细胞命运决定。
