title: Bromodomain protein BRD4 is required for estrogen receptor-dependent enhancer activation and gene transcription.
abstract: The estrogen receptor α (ERα) controls cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to control gene transcription. A deeper understanding of these transcriptional mechanisms may uncover therapeutic targets for ERα-dependent cancers. We show that BRD4 regulates ERα-induced gene expression by affecting elongation-associated phosphorylation of RNA polymerase II (RNAPII) and histone H2B monoubiquitination. Consistently, BRD4 activity is required for proliferation of ER(+) breast and endometrial cancer cells and uterine growth in mice. Genome-wide studies revealed an enrichment of BRD4 on transcriptional start sites of active genes and a requirement of BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we demonstrate that BRD4 occupancy on distal EREs enriched for H3K27ac is required for recruitment and elongation of RNAPII on EREs and the production of ERα-dependent enhancer RNAs. These results uncover BRD4 as a central regulator of ERα function and potential therapeutic target.
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany; Institute for Molecular Oncology, University Medical Center Göttingen, 37077 Göttingen, Germany; Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Sankari
authors.initials: S
authors.lastname: Nagarajan
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany; Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Tareq
authors.initials: T
authors.lastname: Hossan
authors.affiliation: Bioinformatics Service Facility, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Heinrich Pette Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors.forename: Malik
authors.initials: M
authors.lastname: Alawi
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany; Institute for Molecular Oncology, University Medical Center Göttingen, 37077 Göttingen, Germany; Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Zeynab
authors.initials: Z
authors.lastname: Najafova
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Indenbirken
authors.affiliation: Institute for Molecular Oncology, University Medical Center Göttingen, 37077 Göttingen, Germany; Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Upasana
authors.initials: U
authors.lastname: Bedi
authors.affiliation: Heisenberg-Group for Molecular Skeletal Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Taipaleenmäki
authors.affiliation: Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ben-Batalla
authors.affiliation: Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Scheller
authors.affiliation: Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Loges
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Target Discovery Institute, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Heisenberg-Group for Molecular Skeletal Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Hesse
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX 75390-8807, USA.
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chiang
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Grundhoff
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany; Institute for Molecular Oncology, University Medical Center Göttingen, 37077 Göttingen, Germany; Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: steven.johnsen@med.uni-goettingen.de.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Johnsen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D047628:Estrogen Receptor alpha; D006657:Histones; D009687:Nuclear Proteins; D012319:RNA Polymerase II; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins