title: Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA.
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.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Stratton
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
authors.forename: Priti
authors.initials: P
authors.lastname: Anand
authors.affiliation: 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.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Tatman
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Ferguson
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Sean T
authors.initials: ST
authors.lastname: Wickers
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Amrut V
authors.initials: AV
authors.lastname: Ambardekar
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Sucharov
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: 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.
authors.forename: Saptarsi M
authors.initials: SM
authors.lastname: Haldar
authors.affiliation: 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.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000107:Acetylation; D000818:Animals; D018797:Cell Cycle Proteins; D002843:Chromatin / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D012319:RNA Polymerase II / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D061805:Transcription Elongation, Genetic / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D024363:Transcription Initiation Site / Q000502:physiology; D000092468:Bromodomain Containing Proteins
chemical_list: D020413:3' Untranslated Regions; D018797:Cell Cycle Proteins; D002843:Chromatin; D035683:MicroRNAs; D009687:Nuclear Proteins; D012319:RNA Polymerase II; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C541874:MIRN92 microRNA, human