Bromodomain Protein BRD4 Is Required for Estrogen Receptor-Dependent Enhancer Activation and Gene Transcription

Sankari Nagarajan, Tareq Hossan, Malik Alawi, Zeynab Najafova, Daniela Indenbirken, Upasana Bedi, Hanna Taipaleenmäki, Isabel Ben-Batalla, Marina Scheller, Sonja Loges, Stefan Knapp, Eric Hesse, Cheng Ming Chiang, Adam Grundhoff, Steven Johnsen

Research output: Contribution to journalArticle

84 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)460-469
Number of pages10
JournalCell reports
Volume8
Issue number2
DOIs
StatePublished - Jul 24 2014
Externally publishedYes

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Transcription
Estrogen Receptors
Transcriptional Activation
Genes
Chemical activation
Estrogens
Response Elements
Proteins
RNA Polymerase II
Elongation
Cell proliferation
Endometrial Neoplasms
Gene expression
Histones
Catalytic Domain
Carcinogenesis
Cells
Cell Proliferation
Genome
RNA

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.

In: Cell reports, Vol. 8, No. 2, 24.07.2014, p. 460-469.

Research output: Contribution to journalArticle

Nagarajan, S, Hossan, T, Alawi, M, Najafova, Z, Indenbirken, D, Bedi, U, Taipaleenmäki, H, Ben-Batalla, I, Scheller, M, Loges, S, Knapp, S, Hesse, E, Chiang, CM, Grundhoff, A & Johnsen, S 2014, 'Bromodomain Protein BRD4 Is Required for Estrogen Receptor-Dependent Enhancer Activation and Gene Transcription', Cell reports, vol. 8, no. 2, pp. 460-469. https://doi.org/10.1016/j.celrep.2014.06.016
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. / Bromodomain Protein BRD4 Is Required for Estrogen Receptor-Dependent Enhancer Activation and Gene Transcription. In: Cell reports. 2014 ; Vol. 8, No. 2. pp. 460-469.
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