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Homo sapiens

ABSTRACT: Effect of cortistatin A (CA) on enhancer occupancy in CA-sensitive and -insensitive human cell lines

OTHER RELATED OMICS DATASETS IN: GSE65161

PROVIDER: PRJNA273301 | ENA |

REPOSITORIES: ENA

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Effect in HCT116 cells of 3hr cortistatin A treatment on gene expression.

Project description:We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation. In this series, we examine the transcriptional effect on insensitive HCT116 cells of 3hrs exposure to CA.

2015-09-25 | GSE65030 | GEO

Effect of cortistatin A (CA) on enhancer occupancy in CA-sensitive and -insensitive human cell lines

Project description:We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation. In this series, we use ChIP-seq of H3K27ac, H3K4me1, MED1, CDK8, BRD4, and RNA polymerase II (PolII) to examine enhancer occupancy and transcriptional response to CA in human cells lines.

2015-09-25 | GSE65138 | GEO

Effect in MOLM-14 cells of 24hr cortistatin A treatment on gene expression

2015-09-25 | GSE65014 | GEO

Effect of 4hr cortistatin A treatment on gene expression in SET2 cells.

2015-09-25 | GSE65105 | GEO

Effect in MV4;11 cells of 3hr cortistatin A treatment on gene expression

2015-09-25 | GSE65019 | GEO

Effect in K562 cells of 3hr cortistatin A treatment on gene expression

2015-09-25 | GSE65012 | GEO

Effect in MOLM-14 cells of 3hr cortistatin A treatment on gene expression

2015-09-25 | GSE65015 | GEO

Mediator kinase inhibition further activates super-enhancer-associated genes in AML

Project description:Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6. The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML. This SuperSeries is composed of the SubSeries listed below.

2015-09-25 | GSE65161 | GEO

Homo sapiens

Project description:Mapping STAT1 pS727 occupancy and effect of cortistatin A (CA) on STAT1 occupancy in JAK2-driven neoplasms

| PRJNA392122 | ENA

Mapping STAT1 pS727 occupancy and effect of cortistatin A (CA) on STAT1 occupancy in JAK2-driven neoplasms

Project description:We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation. In this series, we use ChIP-seq of STAT1 and STAT1 pS727 to examine how the localization of STAT1 is affected by inhibition of serine 727 phosphorylation

2018-04-11 | GSE100566 | GEO

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