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Status |
Public on Aug 06, 2013 |
Title |
BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure [ChIP-Seq] |
Organism |
Mus musculus |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
Heart failure is driven by the interplay between master regulatory transcription factors and dynamic alterations in chromatin structure. Coordinate activation of developmental, inflammatory, fibrotic and growth regulators underlies the hallmark phenotypes of pathologic cardiac hypertrophy and contractile failure. While transactivation in this context is known to be associated with recruitment of histone acetyl-transferase enzymes and local chromatin hyperacetylation, the role of epigenetic reader proteins in cardiac biology is unknown. We therefore undertook a first study of acetyl-lysine reader proteins, or bromodomains, in heart failure. Using a chemical genetic approach, we establish a central role for BET-family bromodomain proteins in gene control during the evolution of heart failure. BET inhibition suppresses cardiomyocyte hypertrophy in a cell-autonomous manner, confirmed by RNA interference in vitro. Following both pressure overload and neurohormonal stimulation, BET inhibition potently attenuates pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to activation of canonical master regulators and effectors that are central to heart failure pathogenesis. Specifically, BET bromodomain inhibition in mice abrogates pathology-associated pause release and transcriptional elongation, thereby preventing activation of cardiac transcriptional pathways relevant to the gene expression profile of failing human hearts. This study implicates epigenetic readers in cardiac biology and identifies BET co-activator proteins as therapeutic targets in heart failure.
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Overall design |
ChIP-Seq of mouse heart tissues from mice induced with heart failure and treated with JQ1 BET bromodomain inhibitor
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Contributor(s) |
Priti A, Brown JD, Lin CY, Bradner JE, Haldar SM |
Citation(s) |
23911322 |
Submission date |
May 06, 2013 |
Last update date |
May 15, 2019 |
Contact name |
James Bradner |
E-mail(s) |
bradner_computation@dfci.harvard.edu
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Organization name |
Dana-Farber Cancer Institute
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Department |
Medical Oncology
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Lab |
Bradner Lab
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Street address |
450 Brookline
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City |
Boston |
State/province |
MA |
ZIP/Postal code |
02215 |
Country |
USA |
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Platforms (2) |
GPL9250 |
Illumina Genome Analyzer II (Mus musculus) |
GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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Samples (13)
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This SubSeries is part of SuperSeries: |
GSE48112 |
BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure |
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Relations |
BioProject |
PRJNA201438 |
SRA |
SRP022134 |