Dept. Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691 Stockholm, Sweden.
Dept. Genome Sciences, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2600, Australia.
Nucleic Acids Res. 2020 May 21;48(9):4877-4890. doi: 10.1093/nar/gkaa234.
A correlation between histone acetylation and transcription has been noted for a long time, but little is known about what step(s) in the transcription cycle is influenced by acetylation. We have examined the immediate transcriptional response to histone deacetylase (HDAC) inhibition, and find that release of promoter-proximal paused RNA polymerase II (Pol II) into elongation is stimulated, whereas initiation is not. Although histone acetylation is elevated globally by HDAC inhibition, less than 100 genes respond within 10 min. These genes are highly paused, are strongly associated with the chromatin regulators NURF and Trithorax, display a greater increase in acetylation of the first nucleosomes than other genes, and become transcriptionally activated by HDAC inhibition. Among these rapidly up-regulated genes are HDAC1 (Rpd3) and subunits of HDAC-containing co-repressor complexes, demonstrating feedback regulation upon HDAC inhibition. Our results suggest that histone acetylation stimulates transcription of paused genes by release of Pol II into elongation, and that increased acetylation is not a consequence of their enhanced expression. We propose that HDACs are major regulators of Pol II pausing and that this partly explains the presence of HDACs at active genes.
长期以来，人们一直注意到组蛋白乙酰化与转录之间存在相关性，但对于乙酰化影响转录周期的哪个步骤知之甚少。我们研究了组蛋白脱乙酰酶 (HDAC) 抑制后的即刻转录反应，发现启动子近端暂停的 RNA 聚合酶 II (Pol II) 进入延伸过程的释放受到刺激，而起始不受影响。尽管 HDAC 抑制会使组蛋白乙酰化整体升高，但在 10 分钟内仅有不到 100 个基因发生反应。这些基因高度暂停，与染色质调节剂 NURF 和 Trithorax 强烈相关，第一个核小体的乙酰化增加幅度大于其他基因，并且通过 HDAC 抑制而被转录激活。在这些快速上调的基因中包括 HDAC1（Rpd3）和包含 HDAC 的共抑制复合物的亚基，这表明在 HDAC 抑制后存在反馈调节。我们的结果表明，组蛋白乙酰化通过将 Pol II 释放到延伸过程中刺激暂停基因的转录，并且增加的乙酰化不是其表达增强的结果。我们提出，HDAC 是 Pol II 暂停的主要调节剂，这部分解释了 HDAC 存在于活性基因中的原因。
