Greer Celeste B, Tanaka Yoshiaki, Kim Yoon Jung, Xie Peng, Zhang Michael Q, Park In-Hyun, Kim Tae Hoon
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Department of Genetics and Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell Rep. 2015 Nov 17;13(7):1444-1455. doi: 10.1016/j.celrep.2015.10.013. Epub 2015 Nov 5.
Transcription elongation regulates the expression of many genes, including oncogenes. Histone deacetylase (HDAC) inhibitors (HDACIs) block elongation, suggesting that 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, HDACIs reduce enhancer activity, as measured by enhancer RNA production. Therefore, 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.
转录延伸调控包括癌基因在内的许多基因的表达。组蛋白去乙酰化酶（HDAC）抑制剂（HDACIs）会阻断延伸过程，这表明HDAC参与基因激活。为了弄清楚这一点，我们在用小分子抑制剂干扰延伸后，对全基因组范围内的新生转录和延伸因子结合情况进行了分析。我们发现HDACI介导的抑制作用需要热休克蛋白90（HSP90）的活性。HDACIs促进RNA聚合酶II（RNAP2）和负性延伸因子（NELF，一种由HSP90稳定的复合物）在相同基因组位点的结合。此外，HDACIs会重新分布含溴结构域蛋白4（BRD4），这是一种参与增强子活性的关键延伸因子。BRD4会结合新乙酰化的位点，其在启动子和增强子处的占据率会降低。此外，通过增强子RNA产生来衡量，HDACIs会降低增强子活性。因此，HDAC对于限制基因体内和基因间区域的乙酰化是必需的。这有利于延伸因子与适当乙酰化的启动子和增强子结合，以实现高效延伸。
