Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment [RNA-seq]

ABSTRACT: Cancer arises from the malignant interplay between oncogenic signaling and cell specification. Transcriptionally activated stem, growth and survival programs reshape an epigenomic identity defined by a transcriptional core regulatory circuitry. To study and disrupt oncogenic transcription, we first created inhibitors of BET bromodomains. Selective antagonism of oncogenic transcriptional signaling arises from bromodomain-specific activity. Recently, we innovated a strategy to induce selective and pronounced degradation of BET coactivator proteins via phthalimide conjugation for E3 ubiquitin ligase recruitment. Degraders of BET bromdomains (dBETs) exhibited superior efficacy to bromodomain inhibitors in cultivated leukemia cells, through unknown mechanisms. Here, we use chemically optimized small-molecule degronimids and kinetic measures of chromatin structure and function to unveil an unrecognized, essential role for BRD4 in the control of global productive transcriptional elongation. Rapid loss of BRD4 attenuates phosphorylation of the carboxy-terminal domain of RNA polymerase II, independent of genomewide recruitment of CDK9 to promoters, leading to a collapse of the transcriptional core regulatory circuitry. These mechanistic studies are performed in translational models of T-cell acute lymphoblastic leukemia, a disease emblematic for transcriptional addiction, to establish a rationale for human clinical investigation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE79253 | GEO | 2017/09/18

SECONDARY ACCESSION(S): PRJNA315414

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Acute loss of BRD4 halts global transcriptional elongation and collapses the core regulatory circuitry of acute lymphoblastic leukemia [RNA-Seq]

Project description:Cancer arises from the malignant interplay between oncogenic signaling and cell specification. Transcriptionally activated stem, growth and survival programs reshape an epigenomic identity defined by a transcriptional core regulatory circuitry. To study and disrupt oncogenic transcription, we first created inhibitors of BET bromodomains. Selective antagonism of oncogenic transcriptional signaling arises from bromodomain-specific activity. Recently, we innovated a strategy to induce selective and pronounced degradation of BET coactivator proteins via phthalimide conjugation for E3 ubiquitin ligase recruitment. Degraders of BET bromdomains (dBETs) exhibited superior efficacy to bromodomain inhibitors in cultivated leukemia cells, through unknown mechanisms. Here, we use chemically optimized small-molecule degronimids and kinetic measures of chromatin structure and function to unveil an unrecognized, essential role for BRD4 in the control of global productive transcriptional elongation. Rapid loss of BRD4 attenuates phosphorylation of the carboxy-terminal domain of RNA polymerase II, independent of genomewide recruitment of CDK9 to promoters, leading to a collapse of the transcriptional core regulatory circuitry. These mechanistic studies are performed in translational models of T-cell acute lymphoblastic leukemia, a disease emblematic for transcriptional addiction, to establish a rationale for human clinical investigation. RNA-Seq for DMSO, dBET6, or JQ1 treated MOLT4 cells

2016-04-01 | E-GEOD-79253 | biostudies-arrayexpress

BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment [ChIP-seq]

2017-09-18 | GSE79288 | GEO

BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment [NET-seq]

2017-09-18 | GSE79271 | GEO

Combined targeting of the BRD4-NUT-p300 axis in NUT midline carcinoma by dual selective bromodomain inhibitor, NEO2734

Project description:NUT midline carcinoma (NMC) is a rare, aggressive subtype of squamous carcinoma that is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and NUT recruits the p300 histone acetyltransferse (HAT) to activate transcription of oncogenic target genes. BET selective bromodomain inhibitors have demonstrated on-target activity in NMC patients, but with limited efficacy. P300, like BRD4, contains a bromodomain. We show that combining selective p300/CBP and BET bromodomain inhibitors, GNE-781 and OTX015, respectively, induces synergistic inhibition of NMC growth. Treatment of NMC cells with the novel dual p300/CBP and BET bromodomain selective inhibitor, NEO2734, potently inhibits growth and induces differentiation of NMC cells in vitro; findings that correspond with potentiated transcriptional effects from combined BET and p300 bromodomain inhibition. In three disseminated NMC xenograft models, NEO2734 provided greater growth inhibition, with tumor regression and significant survival benefit seen in two of three models, compared with a lead clinical BET inhibitor or 'standard' chemotherapy.

2020-06-19 | GSE142481 | GEO

Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers [Affymetrix]

Project description:Chromatin regulators have become highly attractive targets for cancer therapy, yet many of these regulators are expressed in a broad range of healthy cells and contribute generally to gene expression. An important conundrum has thus emerged: how can inhibition of a general regulator of gene expression produce selective effects at specific oncogenes? Here we investigate how inhibition of the transcriptional coactivator BRD4 (Bromodomain containing 4) leads to selective inhibition of disease-critical oncogenes in a highly malignant blood cancer, multiple myeloma (MM). We found that BRD4 generally occupies the promoter elements of active genes together with the Mediator coactivator, but remarkably high levels of these two coactivator proteins were associated with a small set of exceptionally large enhancers. These super-enhancers are associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impact genes with super-enhancers, including the c-MYC oncogene. Super-enhancers were found at key oncogenic drivers in many other tumor cells. Thus, super-enhancers can regulate oncogenic drivers in tumor cells, which in some cells can be preferentially disrupted by BRD4 inhibition, which in turn contributes to the selective transcriptional effects observed at these oncogenes. These observations have implications for the discovery of novel cancer therapeutics directed at components of super-enhancers in diverse tumor types. Gene expression profiling in multiple myeloma cells after BET-Bromodomain inhibition with JQ1

2013-03-07 | E-GEOD-44929 | biostudies-arrayexpress

Discovery and Characterization of Super-Enhancer Associated Dependencies in Diffuse Large B-Cell Lymphoma

Project description:Diffuse Large B-Cell Lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of BET bromodomain proteins in DLBCL, using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of BRD4 at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease. ChIP-Seq for various transcription factors and histone modifications in diffuse large B-cell lymphoma cells

2013-12-10 | E-GEOD-46663 | biostudies-arrayexpress

Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer (ChIP-Seq)

Project description:Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling1-3. Despite the success of recently approved therapies targeting AR signaling such as abiraterone4-6 and second generation anti-androgens MDV3100 (enzalutamide)7,8, durable responses are limited, presumably due to acquired resistance. Recently JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies9-12. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ111,13. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. Examination of AR, BRD2, BRD3, BRD4, ERG, RNA Pol II and H3K27ac in prostate cancer cells with respect to BET inhibitors

2014-04-25 | E-GEOD-55062 | biostudies-arrayexpress

Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers

Project description:Chromatin regulators have become highly attractive targets for cancer therapy, yet many of these regulators are expressed in a broad range of healthy cells and contribute generally to gene expression. An important conundrum has thus emerged: how can inhibition of a general regulator of gene expression produce selective effects at specific oncogenes? Here we investigate how inhibition of the transcriptional coactivator BRD4 (Bromodomain containing 4) leads to selective inhibition of disease-critical oncogenes in a highly malignant blood cancer, multiple myeloma (MM). We found that BRD4 generally occupies the promoter elements of active genes together with the Mediator coactivator, but remarkably high levels of these two coactivator proteins were associated with a small set of exceptionally large enhancers. These super-enhancers are associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impact genes with super-enhancers, including the c-MYC oncogene. Super-enhancers were found at key oncogenic drivers in many other tumor cells. Thus, super-enhancers can regulate oncogenic drivers in tumor cells, which in some cells can be preferentially disrupted by BRD4 inhibition, which in turn contributes to the selective transcriptional effects observed at these oncogenes. These observations have implications for the discovery of novel cancer therapeutics directed at components of super-enhancers in diverse tumor types. ChIP-Seq for chromatin regulators and RNA Polymerase II in multiple myeloma, glioblastoma multiforme, and small cell lung cancer

2013-01-02 | E-GEOD-42355 | biostudies-arrayexpress

Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer (microarray)

2014-04-25 | E-GEOD-55063 | biostudies-arrayexpress

Targeting the MLL complex in castration-resistant prostate cancer [ChIP-seq]

Project description:Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling. Despite the success of recently approved therapies targeting AR signaling, such as abiraterone and second-generation anti-androgens MDV3100 (enzalutamide), durable responses are limited, presumably due to acquired resistance. Recently, JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. Examination of ASH2L genome-wide binding in prostate cancer cells after AR stimulation.

2015-03-02 | E-GEOD-60841 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data