BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones

Kanno, Takuji; Kanno, Yuka; LeRoy, Gary; Campos, Eric I.; Sun, Hong; Brooks, Stephen R.; Vahedi, Golnaz; Heightman, Tom D.; Garcia, Benjamin A.; Reinberg, Danny; Siebenlist, Ulrich; O’Shea, John J.; Ozato, Keiko

doi:10.1038/nsmb.2912

Cited by 254 publications

(259 citation statements)

References 75 publications

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“…In unstimulated cells, BRD4's affinity for binding diacetylated histone H4 (on Lys 5, 8, and 12) and H3 (on Lys 9 and 16) results in its primary distribution throughout the genome associated with H3K27-Ac-enriched enhancers of actively expressed genes (57). Although a number of studies have implicated BRD4 in control of housekeeping gene expression, BRD4 interaction is dynamically reconfigured through indirect transcription factor interaction and directly binding acetylated Lys side chains of regulatory histones.…”

Section: Discussionmentioning

confidence: 99%

BRD4 Couples NF-κB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection

Tian

Yang

Zhao

et al. 2017

J Virol

129

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The airway mucosa expresses protective interferon (IFN) and inflammatory cytokines in response to respiratory syncytial virus (RSV) infection. In this study, we examine the role of bromodomain containing 4 (BRD4) in mediating this innate immune response in human small airway epithelial cells. We observe that RSV induces BRD4 to complex with NF-B/RelA. BRD4 is functionally required for expression of the NF-Bdependent inflammatory gene regulatory network (GRN), including the IFN response factor 1 (IRF1) and IRF7, which mediate a cross talk pathway for RIG-I upregulation. Mechanistically, BRD4 is required for cyclin-dependent kinase 9 (CDK9) recruitment and phospho-Ser 2 carboxy-terminal domain (CTD) RNA polymerase (Pol) II formation on the promoters of IRF1, IRF7, and RIG-I, producing their enhanced expression by transcriptional elongation. We also find that BRD4 independently regulates CDK9/ phospho-Ser 2 CTD RNA Pol II recruitment to the IRF3-dependent IFN-stimulated genes (ISGs). In vivo, poly(I·C)-induced neutrophilia and mucosal chemokine production are blocked by a small-molecule BRD4 bromodomain inhibitor. Similarly, BRD4 inhibition reduces RSV-induced neutrophilia, mucosal CXC chemokine expression, activation of the IRF7-RIG-I autoamplification loop, mucosal IFN expression, and airway obstruction. RSV infection activates BRD4 acetyltransferase activity on histone H3 Lys (K) 122, demonstrating that RSV infection activates BRD4 in vivo. These data validate BRD4 as a major effector of RSV-induced inflammation and disease. BRD4 is required for coupling NF-B to expression of inflammatory genes and the IRF-RIG-I autoamplification pathway and independently facilitates antiviral ISG expression. BRD4 inhibition may be a strategy to reduce exuberant virus-induced mucosal airway inflammation. IMPORTANCEIn the United States, 2.1 million children annually require medical attention for RSV infections. A first line of defense is the expression of the innate gene network by infected epithelial cells. Expression of the innate response requires the recruitment of transcriptional elongation factors to rapidly induce innate response genes through an unknown mechanism. We discovered that RSV infection induces a complex of bromodomain containing 4 (BRD4) with NF-B and cyclindependent kinase 9 (CDK9). BRD4 is required for stable CDK9 binding, phosphoSer 2 RNA Pol II formation, and histone acetyltransferase activity. Inhibition of BRD4 blocks Toll-like receptor 3 (TLR3)-dependent neutrophilia and RSV-induced inflammation, demonstrating its importance in the mucosal innate response in vivo. Our study shows that BRD4 plays a central role in inflammation and activation of the IRF7-RIG-I amplification loop vital for mucosal interferon expression. BRD4 inhibition may be a strategy for modulating exuberant mucosal airway inflammation.

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Section: Discussionmentioning

confidence: 99%

BRD4 Couples NF-κB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection

Tian

Yang

Zhao

et al. 2017

J Virol

129

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“…Interestingly, BRD4 may show widespread localization in noncoding regions of the genome. Indeed, a recent report shows that BRD4 occupies vast genomic regions in mouse cells, where it assists the elongation of coding and noncoding transcripts originating from enhancer regions (eRNAs) (51).…”

Section: Discussionmentioning

confidence: 99%

The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

Pastori

Kapranov

Penas

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

179

152

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Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumorpromoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases.glioblastoma | long noncoding RNAs | epigenetics | BRD4 | I-BET151

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“…In fact, BRD4 itself has been shown to regulate eRNA expression in murine cells (67). To explore the connection between eRNAs and BET activity at the cMYC locus, we asked whether other superenhancers adjacent to the cMYC locus express jci.org Volume 126…”

Section: Ccat1 Pcat1 and Loc728724 Are Bet Transcriptional Targets mentioning

confidence: 99%

CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer

McCleland¹,

Mesh²,

Lorenzana³

et al. 2016

Journal of Clinical Investigation

199

167

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BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones

Cited by 254 publications

References 75 publications

BRD4 Couples NF-κB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection

BRD4 Couples NF-κB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection

The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer

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