title: Histone Deacetylases Positively Regulate Transcription through the Elongation Machinery.
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.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Celeste B
authors.initials: CB
authors.lastname: Greer
authors.affiliation: Department of Genetics and Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Biological Sciences and Center for Systems Biology, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences and Center for Systems Biology, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Xie
authors.affiliation: Department of Biological Sciences and Center for Systems Biology, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Michael Q
authors.initials: MQ
authors.lastname: Zhang
authors.affiliation: Department of Genetics and Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: In-Hyun
authors.initials: IH
authors.lastname: Park
authors.affiliation: Department of Biological Sciences and Center for Systems Biology, The University of Texas at Dallas, Richardson, TX 75080, USA. Electronic address: genome@utdallas.edu.
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012319:RNA Polymerase II / Q000378:metabolism; D061805:Transcription Elongation, Genetic; D014157:Transcription Factors / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D009687:Nuclear Proteins; D012319:RNA Polymerase II; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins