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Cell Rep. 2016 Aug 2;16(5):1366-1378. doi: 10.1016/j.celrep.2016.06.074. Epub 2016 Jul 14.

Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA.

Author information

1
Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
3
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
4
Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA; Medical Scientist Training Program, University of Colorado Denver, Aurora, CO 80045, USA.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
6
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Division of Cardiology, Department of Medicine and Cardiovascular Research Institute, UCSF School of Medicine, San Francisco, CA 94143, USA.
7
Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA; Medical Scientist Training Program, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address: timothy.mckinsey@ucdenver.edu.

Abstract

BRD4 governs pathological cardiac gene expression by binding acetylated chromatin, resulting in enhanced RNA polymerase II (Pol II) phosphorylation and transcription elongation. Here, we describe a signal-dependent mechanism for the regulation of BRD4 in cardiomyocytes. BRD4 expression is suppressed by microRNA-9 (miR-9), which targets the 3' UTR of the Brd4 transcript. In response to stress stimuli, miR-9 is downregulated, leading to derepression of BRD4 and enrichment of BRD4 at long-range super-enhancers (SEs) associated with pathological cardiac genes. A miR-9 mimic represses stimulus-dependent targeting of BRD4 to SEs and blunts Pol II phosphorylation at proximal transcription start sites, without affecting BRD4 binding to SEs that control constitutively expressed cardiac genes. These findings suggest that dynamic enrichment of BRD4 at SEs genome-wide serves a crucial role in the control of stress-induced cardiac gene expression and define a miR-dependent signaling mechanism for the regulation of chromatin state and Pol II phosphorylation.

PMID:
27425608
PMCID:
PMC4972677
DOI:
10.1016/j.celrep.2016.06.074
[Indexed for MEDLINE]
Free PMC Article

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