Histone Deacetylases Positively Regulate Transcription through the Elongation Machinery.
Histone Deacetylases Positively Regulate Transcription through the Elongation Machinery.
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DOI：
10.1016/j.celrep.2015.10.013
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发表时间：
2015-11-17
期刊：
影响因子：
8.8
通讯作者：
Kim TH
中科院分区：
文献类型：
--
作者：
Greer CB;Tanaka Y;Kim YJ;Xie P;Zhang MQ;Park IH;Kim TH
转录伸长调节许多基因的表达，包括致癌基因。组蛋白去乙酰化酶（HDAC）抑制剂（HDAC）阻断延伸，表明HDAC参与基因激活。为了理解这一点，我们分析了小分子抑制剂干扰延伸后的新生转录和延伸因子结合全基因组。我们发现hdac介导的抑制需要热休克蛋白90 （HSP90）活性。hdac促进RNA聚合酶II （RNAP2）和负延伸因子（NELF）在相同基因组位点的结合，NELF是一种由HSP90稳定的复合物。此外，hdac重新分配含溴结构域蛋白4 (BRD4)，这是一个参与增强子活性的关键延伸因子：BRD4结合到新乙酰化的位点上，其在启动子和增强子上的占用减少。此外，通过增强子RNA的产生，HDACI降低了增强子的活性。因此，hdac是限制基因体和基因间区域乙酰化所必需的。这有助于将延伸因子与乙酰化的启动子和增强子结合，从而实现有效的延伸。
Transcription elongation regulates the expression of many genes, including oncogenes. Histone deacetylase (HDAC) inhibitors (HDACIs) block elongation, suggesting HDACs are involved in gene activation. To understand this, we analyzed nascent transcription and elongation factor binding genome-wide after perturbation of elongation with small molecule inhibitors. We found that HDACI-mediated repression requires heat shock protein 90 (HSP90) activity. HDACIs promote the association of RNA polymerase II (RNAP2) and negative elongation factor (NELF), a complex stabilized by HSP90, at the same genomic sites. Additionally, HDACIs redistribute bromodomain-containing protein 4 (BRD4), a key elongation factor involved in enhancer activity: BRD4 binds to newly acetylated sites, and its occupancy at promoters and enhancers is reduced. Furthermore, HDACI reduce enhancer activity as measured by enhancer RNA production. Thus, HDACs are required for limiting acetylation in gene bodies and intergenic regions. This facilitates the binding of elongation factors to properly acetylated promoters and enhancers for efficient elongation.