Regulation of GLI underlies a role for BET bromodomains in pancreatic cancer growth and the tumor microenvironment
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE55209 | GEO | 2016/09/08
SECONDARY ACCESSION(S): PRJNA238900
REPOSITORIES: GEO
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is extraordinarily chemoresistant and the abundant stromal content of these tumors contributes to the ineffective treatment of this disease. While the genetic alterations of PDAC have been well characterized, the epigenetic pathways regulating PDAC remain, for the most part, elusive. Employing an in vivo shRNA screen targeting epigenetic regulators, we identified members of the BET family of chromatin adaptors as key regulators of PDAC cell growth and maintenance of the tumor stroma. BET family members contribute to PDAC cell growth by modulating the activity of two key transcriptional programs, MYC and GLI. Within the cancer cells, BET inhibition also results in down-regulation of a key mediator of the tumor microenvironment, SHH, corresponding to a decrease in the stromal content of tumors. Taken together, these results suggest that therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Total RNA was isolated from 4 untreated PDAC cell lines or those exposedto the BET bromodomain inhibibitor CPI203 (1.6 uM) or control DMSO for 5 and 10 hours
2016-09-08 | E-GEOD-55209 | biostudies-arrayexpress
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
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
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
Project description:The evolutionarily conserved BET bromodomain family contain a distinctive tandem bromodomain structure that enables their chromatin binding to facilitate transcription. Whilst first-in-class drugsthat equally inhibit both bromodomains have shown pre-clinicaland clinical efficacy in a range of malignant and inflammatory pathologies, the functional contribution of the first (BD1) and second (BD2) bromodomains to these pathologies remains largely unknown. Here we haveexploited detailedstructuralinsights and our extensivemedicinal chemistry capabilities to develop novel compounds that are exquisitely selectivefor either BD1 or BD2 of the BET proteins. Using thesewell characterised domain-specific inhibitors we show that BD1 is required by all BET proteins to associate with chromatin and maintain established malignant transcriptional programs.Therefore, targeting BD1 alone phenocopies the therapeutic effects of current non-selective BET inhibitorsin models of cancer. Whilst steady state gene expression primarily requires BD1,we find that the rapid increase of gene expression effectedby a wide range of inflammatory stimuli requiresboth BD1 and BD2. Moreover, although BRD4 is the principal member required for the maintenance of established gene expression, efficient gene induction also requires BRD2 and BRD3. Selective inhibition of BD2 is effective in perturbing the recruitment of all the BET proteins for stimulated gene expression and consequently small molecule inhibitors of BD2 amelioratethe immunoinflammatory end organ damage seen in models of inflammatory arthritis, psoriasis and hepatitis. Together,these data provide novel biological and functional insights into this family of key transcriptional regulators. Importantly, they also help refine the future therapeutic approach when targeting the BET proteinsin distinct pathologies such as cancer and immuno-inflammation.
2020-06-17 | GSE138089 | GEO
Project description:The evolutionarily conserved BET bromodomain family contain a distinctive tandem bromodomain structure that enables their chromatin binding to facilitate transcription. Whilst first-in-class drugsthat equally inhibit both bromodomains have shown pre-clinicaland clinical efficacy in a range of malignant and inflammatory pathologies, the functional contribution of the first (BD1) and second (BD2) bromodomains to these pathologies remains largely unknown. Here we haveexploited detailedstructuralinsights and our extensivemedicinal chemistry capabilities to develop novel compounds that are exquisitely selectivefor either BD1 or BD2 of the BET proteins. Using thesewell characterised domain-specific inhibitors we show that BD1 is required by all BET proteins to associate with chromatin and maintain established malignant transcriptional programs.Therefore, targeting BD1 alone phenocopies the therapeutic effects of current non-selective BET inhibitorsin models of cancer. Whilst steady state gene expression primarily requires BD1,we find that the rapid increase of gene expression effectedby a wide range of inflammatory stimuli requiresboth BD1 and BD2. Moreover, although BRD4 is the principal member required for the maintenance of established gene expression, efficient gene induction also requires BRD2 and BRD3. Selective inhibition of BD2 is effective in perturbing the recruitment of all the BET proteins for stimulated gene expression and consequently small molecule inhibitors of BD2 amelioratethe immunoinflammatory end organ damage seen in models of inflammatory arthritis, psoriasis and hepatitis. Together,these data provide novel biological and functional insights into this family of key transcriptional regulators. Importantly, they also help refine the future therapeutic approach when targeting the BET proteinsin distinct pathologies such as cancer and immuno-inflammation.
2020-06-17 | GSE138084 | GEO
Project description:The evolutionarily conserved BET bromodomain family contain a distinctive tandem bromodomain structure that enables their chromatin binding to facilitate transcription. Whilst first-in-class drugsthat equally inhibit both bromodomains have shown pre-clinicaland clinical efficacy in a range of malignant and inflammatory pathologies, the functional contribution of the first (BD1) and second (BD2) bromodomains to these pathologies remains largely unknown. Here we haveexploited detailedstructuralinsights and our extensivemedicinal chemistry capabilities to develop novel compounds that are exquisitely selectivefor either BD1 or BD2 of the BET proteins. Using thesewell characterised domain-specific inhibitors we show that BD1 is required by all BET proteins to associate with chromatin and maintain established malignant transcriptional programs.Therefore, targeting BD1 alone phenocopies the therapeutic effects of current non-selective BET inhibitorsin models of cancer. Whilst steady state gene expression primarily requires BD1,we find that the rapid increase of gene expression effectedby a wide range of inflammatory stimuli requiresboth BD1 and BD2. Moreover, although BRD4 is the principal member required for the maintenance of established gene expression, efficient gene induction also requires BRD2 and BRD3. Selective inhibition of BD2 is effective in perturbing the recruitment of all the BET proteins for stimulated gene expression and consequently small molecule inhibitors of BD2 amelioratethe immunoinflammatory end organ damage seen in models of inflammatory arthritis, psoriasis and hepatitis. Together,these data provide novel biological and functional insights into this family of key transcriptional regulators. Importantly, they also help refine the future therapeutic approach when targeting the BET proteinsin distinct pathologies such as cancer and immuno-inflammation.
2020-06-17 | GSE138209 | GEO
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.
2013-08-06 | GSE48111 | GEO
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.
2013-08-06 | GSE46668 | GEO
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.
2013-08-06 | GSE48110 | GEO