Histone acetylation is a dynamic modification regulated by the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Deacetylation of histone tails results in chromatin tightening, and therefore, HDACs are generally regarded as transcriptional repressors. Counterintuitively, simultaneous deletion of Hdac1 and Hdac2 in embryonic stem cells (ESCs) reduces expression of the pluripotency-associated transcription factors Pou5f1, Sox2, and Nanog (PSN). By shaping global histone acetylation patterns, HDACs indirectly regulate the activity of acetyl-lysine readers, such as the transcriptional activator BRD4. Here, we use inhibitors of HDACs and BRD4 (LBH589 and JQ1, respectively) in combination with precision nuclear run-on and sequencing (PRO-seq) to examine their roles in defining the ESC transcriptome. Both LBH589 and JQ1 cause a marked reduction in the pluripotent gene network. However, although JQ1 treatment induces widespread transcriptional pausing, HDAC inhibition causes a reduction in both paused and elongating polymerase, suggesting an overall reduction in polymerase recruitment. Using enhancer RNA (eRNA) expression to measure enhancer activity, we find that LBH589-sensitive eRNAs are preferentially associated with superenhancers and PSN binding sites. These findings suggest that HDAC activity is required to maintain pluripotency by regulating the PSN enhancer network via the recruitment of RNA polymerase II.

中文翻译：

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组蛋白脱乙酰酶通过将 RNA 聚合酶 II 招募到编码和非编码位点来维持多能基因网络的表达

组蛋白乙酰化是一种动态修饰，受组蛋白乙酰转移酶 (HAT) 和组蛋白脱乙酰酶 (HDAC) 的相反作用调节。组蛋白尾部的脱乙酰化会导致染色质收紧，因此 HDAC 通常被视为转录抑制因子。与直觉相反，胚胎干细胞 (ESC) 中Hdac1和Hdac2的同时缺失会降低多能性相关转录因子Pou5f1、Sox2和Nanog (PSN) 的表达。通过塑造全局组蛋白乙酰化模式，HDAC 间接调节乙酰赖氨酸读取器的活性，例如转录激活剂 BRD4。在这里，我们使用 HDAC 和 BRD4 抑制剂（分别为 LBH589 和 JQ1）与精密核连续测序 (PRO-seq) 相结合，检查它们在定义 ESC 转录组中的作用。 LBH589 和 JQ1 都会导致多能基因网络显着减少。然而，尽管 JQ1 处理会诱导广泛的转录暂停，但 HDAC 抑制会导致暂停聚合酶和延长聚合酶减少，表明聚合酶募集总体减少。使用增强子 RNA (eRNA) 表达来测量增强子活性，我们发现 LBH589 敏感的 eRNA 优先与超级增强子和 PSN 结合位点相关。这些发现表明，HDAC 活性是通过招募 RNA 聚合酶 II 来调节 PSN 增强子网络来维持多能性所必需的。