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 phosphorylationof RNA polymerase II (RNAPII) and histone H2Bmonoubiquitination. Consistently, BRD4 activity isrequired 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 460-469 |
| Number of pages | 10 |
| Journal | Cell Reports |
| Volume | 8 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jul 24 2014 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
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 Reports, Vol. 8, No. 2, 24.07.2014, p. 460-469.Research output: Contribution to journal › Article
}
TY - JOUR
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.
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 phosphorylationof RNA polymerase II (RNAPII) and histone H2Bmonoubiquitination. Consistently, BRD4 activity isrequired 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 phosphorylationof RNA polymerase II (RNAPII) and histone H2Bmonoubiquitination. Consistently, BRD4 activity isrequired 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.
UR - http://www.scopus.com/inward/record.url?scp=84904811353&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904811353&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2014.06.016
DO - 10.1016/j.celrep.2014.06.016
M3 - Article
C2 - 25017071
AN - SCOPUS:84904811353
VL - 8
SP - 460
EP - 469
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 2
ER -