Bromodomain protein BRD4 is required for estrogen receptor-dependent enhancer activation and gene transcription
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Bromodomain protein BRD4 is required for estrogen receptor-dependent enhancer activation and gene transcription. / Nagarajan, Sankari; Hossan, Tareq; Alawi, Malik; Najafova, Zeynab; Indenbirken, Daniela; Bedi, Upasana; Taipaleenmäki, Hanna; Ben-Batalla, Isabel; Scheller, Marina; Loges, Sonja; Knapp, Stefan; Hesse, Eric; Chiang, Cheng-Ming; Grundhoff, Adam; Johnsen, Steven A.
in: CELL REP, Jahrgang 8, Nr. 2, 24.07.2014, S. 459-468.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Bromodomain protein BRD4 is required for estrogen receptor-dependent enhancer activation and gene transcription
AU - Nagarajan, Sankari
AU - Hossan, Tareq
AU - Alawi, Malik
AU - Najafova, Zeynab
AU - Indenbirken, Daniela
AU - Bedi, Upasana
AU - Taipaleenmäki, Hanna
AU - Ben-Batalla, Isabel
AU - Scheller, Marina
AU - Loges, Sonja
AU - Knapp, Stefan
AU - Hesse, Eric
AU - Chiang, Cheng-Ming
AU - Grundhoff, Adam
AU - Johnsen, Steven A
N1 - Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2014/7/24
Y1 - 2014/7/24
N2 - 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.
AB - 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.
U2 - 10.1016/j.celrep.2014.06.016
DO - 10.1016/j.celrep.2014.06.016
M3 - SCORING: Journal article
C2 - 25017071
VL - 8
SP - 459
EP - 468
JO - CELL REP
JF - CELL REP
SN - 2211-1247
IS - 2
ER -