BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones.
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.
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.
Tomohiko
T
Kanno
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
Yuka
Y
Kanno
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
Gary
G
LeRoy
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
Eric
E
Campos
Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
Hong-Wei
HW
Sun
Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
Stephen R
SR
Brooks
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
Golnaz
G
Vahedi
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford, UK.
Tom D
TD
Heightman
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Benjamin A
BA
Garcia
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
Danny
D
Reinberg
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
Ulrich
U
Siebenlist
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
John J
JJ
O'Shea
Program in Genomics of Differentiation, National Institutes of Child Health and Human Development, Bethesda, Maryland, USA.
Keiko
K
Ozato
D000107:Acetylation; D000818:Animals; D004742:Enhancer Elements, Genetic; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D060066:Protein Interaction Maps; D012313:RNA / Q000235:genetics*; D012319:RNA Polymerase II / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics; D061805:Transcription Elongation, Genetic; D014157:Transcription Factors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D061785:Transcription Initiation, Genetic; D000092468:Bromodomain Containing Proteins
D006657:Histones; D009687:Nuclear Proteins; D009707:Nucleosomes; D042925:Positive Transcriptional Elongation Factor B; D012313:RNA; D012319:RNA Polymerase II; D022661:RNA, Untranslated; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins