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Cell Rep. 2015 Nov 17;13(7):1444-55. doi: 10.1016/j.celrep.2015.10.013. Epub 2015 Nov 5.

Histone Deacetylases Positively Regulate Transcription through the Elongation Machinery.

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Department of Genetics and Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Department of Biological Sciences and Center for Systems Biology, The University of Texas at Dallas, Richardson, TX 75080, USA.
4
Department of Biological Sciences and Center for Systems Biology, The University of Texas at Dallas, Richardson, TX 75080, USA. Electronic address: genome@utdallas.edu.

Abstract

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.

PMID:
26549458
PMCID:
PMC4934896
DOI:
10.1016/j.celrep.2015.10.013
[Indexed for MEDLINE]
Free PMC Article
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