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

BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones.

Author information

1
1] Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA. [2] Program in Genomics of Differentiation, National Institutes of Child Health and Human Development, Bethesda, Maryland, USA.
2
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
3
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
4
Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
5
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford, UK.
6
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
7
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
8
Program in Genomics of Differentiation, National Institutes of Child Health and Human Development, Bethesda, Maryland, USA.

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.

PMID:
25383670
PMCID:
PMC4720983
DOI:
10.1038/nsmb.2912
[Indexed for MEDLINE]
Free PMC Article

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