BRD4 Assists Elongation of Both Coding and Enhancer RNAs by Interacting With Acetylated Histones

Nat Struct Mol Biol. 2014 Dec;21(12):1047-57. doi: 10.1038/nsmb.2912. Epub 2014 Nov 10.

Abstract

Small-molecule BET inhibitors interfere with the epigenetic interactions between acetylated histones and the bromodomains of the BET family proteins, including BRD4, and they potently inhibit growth of malignant cells by targeting cancer-promoting genes. BRD4 interacts with the pause-release factor P-TEFb and has been proposed to release RNA polymerase II (Pol II) from promoter-proximal pausing. We show that BRD4 occupies widespread genomic regions in mouse cells and directly stimulates elongation of both protein-coding transcripts and noncoding enhancer RNAs (eRNAs), in a manner dependent on bromodomain function. BRD4 interacts with elongating Pol II complexes and assists Pol II in progression through hyperacetylated nucleosomes by interacting with acetylated histones via bromodomains. On active enhancers, the BET inhibitor JQ1 antagonizes BRD4-associated eRNA synthesis. Thus, BRD4 is involved in multiple steps of the transcription hierarchy, primarily by facilitating transcript elongation both at enhancers and on gene bodies independently of P-TEFb.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Acetylation
  • Animals
  • Enhancer Elements, Genetic
  • HEK293 Cells
  • Histones / metabolism*
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Nuclear Proteins / analysis
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism*
  • Nucleosomes / genetics
  • Nucleosomes / metabolism
  • Positive Transcriptional Elongation Factor B / metabolism
  • Protein Interaction Maps
  • RNA / genetics*
  • RNA Polymerase II / metabolism
  • RNA, Untranslated / genetics
  • Transcription Elongation, Genetic*
  • Transcription Factors / analysis
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism*
  • Transcription Initiation, Genetic

Substances

  • Brd4 protein, mouse
  • Histones
  • Nuclear Proteins
  • Nucleosomes
  • RNA, Untranslated
  • Transcription Factors
  • RNA
  • Positive Transcriptional Elongation Factor B
  • RNA Polymerase II

Associated data

  • GEO/GSE56370
  • GEO/GSE58731