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Series GSE46668 Query DataSets for GSE46668
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
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.
Overall design ChIP-Seq of mouse heart tissues from mice induced with heart failure and treated with JQ1 BET bromodomain inhibitor
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
Organization name Dana-Farber Cancer Institute
Department Medical Oncology
Lab Bradner Lab
Street address 450 Brookline
City Boston
State/province MA
ZIP/Postal code 02215
Country USA
Platforms (2)
GPL9250 Illumina Genome Analyzer II (Mus musculus)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
Samples (13)
This SubSeries is part of SuperSeries:
GSE48112 BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure
BioProject PRJNA201438
SRA SRP022134

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Supplementary file Size Download File type/resource
GSE46668_RAW.tar 1003.0 Mb (http)(custom) TAR (of WIG)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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