Histone Deacetylases Positively Regulate Transcription Through the Elongation Machinery


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.; Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Supplemental information included with article.
BT474 cells, Heat shock protein 90, BRD4 protein, Hystone Deacetylases, Acetylation, vorinostat
C.B.G. has received support from NIH Training Grant GM007324 and a PhRMA foundation predoctoral fellowship. MQZ and PX acknowledge support from NIH Grant R01 MH102616, the Cecil H. and Ida Green Endowment Chair, and a UTD Founder’s Fellowship. I.H.P. is partly supported by NIGMS (GM0099130-01, GM111667-01), the KRIBB/KRCF research initiative program (NAP-09-1), and a CT Stem Cell Grant (13-SCB-YALE-06). Grants to T.H.K. from the Rita Allen Foundation, Sidney Kimmel Foundation for Cancer Research, Yale Comprehensive Cancer Center (CA-16359), Alexander and Margaret Stewart Trust, National Institute of Allergy and Infection Disease (R21AI107067), and National Cancer Institute (R01CA140485) supported this work.
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