Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA
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...
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2016-08-01
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doaj-df7e3bb8863e4f5b8a372f88ea649cde2020-11-25T02:20:58ZengElsevierCell Reports2211-12472016-08-011651366137810.1016/j.celrep.2016.06.074Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNAMatthew S. Stratton0Charles Y. Lin1Priti Anand2Philip D. Tatman3Bradley S. Ferguson4Sean T. Wickers5Amrut V. Ambardekar6Carmen C. Sucharov7James E. Bradner8Saptarsi M. Haldar9Timothy A. McKinsey10Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USADepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USAGladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USADivision of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USADivision of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USADivision of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USADivision of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USADivision of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USAGladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USADivision of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USABRD4 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.http://www.sciencedirect.com/science/article/pii/S2211124716308439 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Matthew S. Stratton Charles Y. Lin Priti Anand Philip D. Tatman Bradley S. Ferguson Sean T. Wickers Amrut V. Ambardekar Carmen C. Sucharov James E. Bradner Saptarsi M. Haldar Timothy A. McKinsey |
spellingShingle |
Matthew S. Stratton Charles Y. Lin Priti Anand Philip D. Tatman Bradley S. Ferguson Sean T. Wickers Amrut V. Ambardekar Carmen C. Sucharov James E. Bradner Saptarsi M. Haldar Timothy A. McKinsey Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA Cell Reports |
author_facet |
Matthew S. Stratton Charles Y. Lin Priti Anand Philip D. Tatman Bradley S. Ferguson Sean T. Wickers Amrut V. Ambardekar Carmen C. Sucharov James E. Bradner Saptarsi M. Haldar Timothy A. McKinsey |
author_sort |
Matthew S. Stratton |
title |
Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA |
title_short |
Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA |
title_full |
Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA |
title_fullStr |
Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA |
title_full_unstemmed |
Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA |
title_sort |
signal-dependent recruitment of brd4 to cardiomyocyte super-enhancers is suppressed by a microrna |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2016-08-01 |
description |
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. |
url |
http://www.sciencedirect.com/science/article/pii/S2211124716308439 |
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