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| Status |
Public on Feb 25, 2020 |
| Title |
Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation [RNA-seq] |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Small molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in pre-clinical models of heart failure (HF). However, the mechanisms by which BRD4 promotes pathological myocardial fibrosis remain unclear. Here, we demonstrate that BRD4 functions as an effector of TGF-b signaling to stimulate conversion of quiescent cardiac fibroblasts into Periostin (Postn)-positive cells that express high levels of extracellular matrix. BRD4 undergoes stimulus-dependent, genome-wide redistribution in cardiac fibroblasts, becoming enriched on a subset of enhancers and super-enhancers, and leading to RNA polymerase II activation and expression of downstream target genes. Employing the SERTA domain-containing protein 4 (Sertad4) locus as a prototype, we demonstrate that dynamic chromatin targeting of BRD4 is controlled, in part, by p38 mitogen-activated protein kinase, and provide evidence of a novel function for Sertad4 in TGF-b-mediated cardiac fibroblast activation. These findings define BRD4 as a central regulator of the pro-fibrotic cell state of cardiac fibroblasts, and establish a signaling circuit for epigenetic reprogramming in HF.
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| Overall design |
RNA-Seq in ARVFs
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| Contributor(s) |
Stratton MS, Bagchi RA, Hirsch RA, Riching AS, Felisbino MB, Enyart BY, Koch KA, Cavasin MA, Alexanian M, Song K, Qi J, Lemieux ME, Lam MP, Haldar SM, Lin CY, McKinsey TA |
| Citation(s) |
31409188 |
| Submission date |
Feb 26, 2019 |
| Last update date |
May 26, 2020 |
| Contact name |
Timothy McKinsey |
| E-mail(s) |
TIMOTHY.MCKINSEY@UCDENVER.EDU
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| Phone |
303-724-5479
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| Organization name |
University of Colorado Anschutz Medical Campus
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| Department |
Division of Cardiology
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| Lab |
McKinsey
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| Street address |
12700 E. 19th Ave (8450E)
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| City |
Aurora |
| State/province |
CO |
| ZIP/Postal code |
80045 |
| Country |
USA |
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| Platforms (1) |
| GPL18694 |
Illumina HiSeq 2500 (Rattus norvegicus) |
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| Samples (9)
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| This SubSeries is part of SuperSeries: |
| GSE127230 |
Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation |
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| Relations |
| BioProject |
PRJNA524373 |
| SRA |
SRP186935 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE127229_cuffnorm_all_fpkm_exprs_raw.txt.gz |
627.0 Kb |
(ftp)(http) |
TXT |
| GSE127229_genes.count_tracking.txt.gz |
552.3 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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