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BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure [Mouse Heart Expression]

ABSTRACT: Heart failure (HF) is driven via interplay between master regulatory transcription factors and dynamic alterations in chromatin structure. While pathologic gene transactivation in this context is known to be associated with recruitment of histone acetyl-transferases 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 HF. Using a chemical genetic approach, we establish a central role for BET-family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and 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 HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers in cardiac biology and identifies BET co-activator proteins as therapeutic targets in HF.

ORGANISM(S): Mus musculus

PROVIDER: GSE48110 | GEO | 2013/08/06

SECONDARY ACCESSION(S): PRJNA208940

REPOSITORIES: GEO

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BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure [Mouse Heart Expression]

Project description:Heart failure (HF) is driven via interplay between master regulatory transcription factors and dynamic alterations in chromatin structure. While pathologic gene transactivation in this context is known to be associated with recruitment of histone acetyl-transferases 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 HF. Using a chemical genetic approach, we establish a central role for BET-family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and 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 HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers in cardiac biology and identifies BET co-activator proteins as therapeutic targets in HF. Gene expression analysis of mouse hearts subjected to either trans aortic constriction (TAC) or sham surgeries followed by treamtent with dmso vehicle or the BET bromodomain inhibitor JQ1

2013-08-06 | E-GEOD-48110 | biostudies-arrayexpress

BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure [NRVM Expression]

Project description:Heart failure (HF) is driven via interplay between master regulatory transcription factors and dynamic alterations in chromatin structure. While pathologic gene transactivation in this context is known to be associated with recruitment of histone acetyl-transferases 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 HF. Using a chemical genetic approach, we establish a central role for BET-family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and 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 HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers in cardiac biology and identifies BET co-activator proteins as therapeutic targets in HF. Gene expression analysis of neonatal rat ventricular mycotes (NRVM) subjected to phenylephrine (PE) treatment followed by treatment with vehicle (DMSO) or the BET bromodomain inhibitor JQ1

2013-08-06 | E-GEOD-48111 | biostudies-arrayexpress

BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure [NRVM Expression]

2013-08-06 | GSE48111 | GEO

BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure [ChIP-Seq]

Project description: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. ChIP-Seq of mouse heart tissues from mice induced with heart failure and treated with JQ1 BET bromodomain inhibitor

2013-08-06 | E-GEOD-46668 | biostudies-arrayexpress

BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure [ChIP-Seq]

2013-08-06 | GSE46668 | GEO

Gene expression data for BET inhibitors

Project description:The BET (bromodomain and extra-terminal) family of acetyl-lysine reader proteins acts as transcriptional activators. BET inhibitors showed anti-cancer efficacies. We performed microarray analysis to characterize BET inhibitor-induced gene expression alterations.

2022-01-01 | GSE168780 | GEO

AMPK links acetyl-coA homeostasis to BET recruitment in acute myeloid leukemia: ChIP-seq

Project description:Altered metabolism fuels two hallmark properties of cancer cells, unlimited proliferation and differentiation blockade. AMP-activated protein kinase (AMPK) is a master regulator of bioenergetics crucial for glucose metabolism in acute myeloid leukemia (AML) and its inhibition delays leukemogenesis, but whether the metabolic function of AMPK alters AML epigenome remains unknown. Here, we demonstrate that AMPK maintains the epigenome of MLL-rearranged AML by linking acetyl-CoA homeostasis to BET bromodomain protein recruitment to chromatin. AMPK deletion reduced acetyl-CoA and histone acetylation, displacing BET proteins from chromatin in leukemia-initiating cells (LICs). In both mouse and patient-derived xenograft AML models, treating with AMPK and BET inhibitors synergistically suppressed AML. Our results provide a therapeutic rationale to target AMPK and BET for AML therapy.

2019-09-05 | GSE128000 | GEO

AMPK links acetyl-coA homeostasis to BET recruitment in acute myeloid leukemia: RNA-seq

2019-09-05 | GSE127999 | GEO

Transcription profiling of mouse model of heart failure rescued by beta-adrenergic receptor kinase (betaARKct), vs heart failure and untreated samples

Project description:Numerous murine models of heart failure (HF) have been described, many of which develop progressive deterioration of cardiac function. We have recently demonstrated that several of these can be "rescued" or prevented by transgenic cardiac expression of a peptide inhibitor of the beta-adrenergic receptor kinase (betaARKct). To uncover genomic changes associated with cardiomyopathy and/or its phenotypic rescue by the betaARKct, oligonucleotide microarray analysis of left ventricular (LV) gene expression was performed in a total of 53 samples, including 12 each of Normal, HF, and Rescue. Multiple statistical analyses demonstrated significant differences between all groups, and further demonstrated that betaARKct Rescue returned gene expression toward that of Normal. In our statistical analyses, we found that the HF phenotype is blindly predictable based solely on gene expression profile. To investigate the progression of HF, LV gene expression was determined in young mice with mildly diminished cardiac function and in older mice with severely impaired cardiac function. Interestingly, mild and advanced HF mice shared similar gene expression profiles and, importantly, the mild HF mice were predicted as having a HF phenotype when blindly subjected to our predictive model described above. These data not only validate our predictive model, but further demonstrate that, in these mice, the HF gene expression profile appears to already be set in the early stages of HF progression. Thus, we have identified methodologies that have the potential to be used for predictive genomic profiling of cardiac phenotype, including cardiovascular disease.

2007-12-13 | E-GEOD-670 | biostudies-arrayexpress

Gene expression data from the heart during regeneration in a zebrafish model of heart failure

Project description:Heart Failure (HF) remains the leading cause of mortality and morbidity globally. Novel therapeutic targets to tackle this pandemic are in dire need. Zebrafish, a vertebrate whose heart shares many physiological similarities to the human heart, are able to naturally undergo cardiac regeneration following HF. We used microarrays to analyse gene expression during cardiac regeneration following heart failure

2021-01-20 | GSE120962 | GEO

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