Super-Enhancers Promote Transcriptional Dysregulation in Nasopharyngeal Carcinoma
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ABSTRACT:
PROVIDER: PRJNA378263 | ENA |
REPOSITORIES: ENA
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Project description:Nasopharyngeal carcinoma (NPC) is an invasive cancer with particularly high incidence in Southeast Asia and Southern China. The pathogenic mechanisms of NPC, particularly those involving epigenetic dysregulation, remain largely elusive, hampering the clinical management of this malignancy. To identify novel druggable targets, we carried out an unbiased high-throughput chemical screening and observed that NPC cells were highly sensitive to cyclin-dependent kinases (CDKs) inhibitors, especially THZ1, a covalent inhibitor of CDK7. THZ1 demonstrated pronounced anti-neoplastic activities both in vitro and in vivo. An integrative analysis using both whole-transcriptome sequencing (RNA-Seq) and chromatin-immunoprecipitation sequencing (ChIP-Seq) pinpointed oncogenic transcriptional amplification mediated by Super-Enhancer (SE) as a key mechanism underlying the vulnerability of NPC cells to THZ1 treatment. Further characterization of SE-mediated network identified many novel SE-associated oncogenic transcripts, such as BCAR1, F3, LDLR, TBC1D2 and a long non-coding RNA, TP53TG1. These transcripts were highly and specifically expressed in NPC, and functionally promoted NPC malignant phenotypes. Moreover, DNA-binding motif analysis within the SE segments suggest that several transcription factors (including ETS2, MAFK and TEAD1) may help establish and maintain SE activity across the genome. Our data together established the landscape of SE-associated oncogenic transcriptional network in NPC, which can be exploited for the development of more effective therapeutic regimen for this disease.
2017-12-01 | GSE95750 | GEO
Project description:Nasopharyngeal carcinoma (NPC) is an invasive cancer with particularly high incidence in Southeast Asia and Southern China. The pathogenic mechanisms of NPC, particularly those involving epigenetic dysregulation, remain largely elusive, hampering the clinical management of this malignancy. To identify novel druggable targets, we carried out an unbiased high-throughput chemical screening and observed that NPC cells were highly sensitive to cyclin-dependent kinases (CDKs) inhibitors, especially THZ1, a covalent inhibitor of CDK7. THZ1 demonstrated pronounced anti-neoplastic activities both in vitro and in vivo. An integrative analysis using both whole-transcriptome sequencing (RNA-Seq) and chromatin-immunoprecipitation sequencing (ChIP-Seq) pinpointed oncogenic transcriptional amplification mediated by Super-Enhancer (SE) as a key mechanism underlying the vulnerability of NPC cells to THZ1 treatment. Further characterization of SE-mediated network identified many novel SE-associated oncogenic transcripts, such as BCAR1, F3, LDLR, TBC1D2 and a long non-coding RNA, TP53TG1. These transcripts were highly and specifically expressed in NPC, and functionally promoted NPC malignant phenotypes. Moreover, DNA-binding motif analysis within the SE segments suggest that several transcription factors (including ETS2, MAFK and TEAD1) may help establish and maintain SE activity across the genome. Our data together established the landscape of SE-associated oncogenic transcriptional network in NPC, which can be exploited for the development of more effective therapeutic regimen for this disease.
2017-12-01 | GSE95749 | GEO
Project description: Not available
| S-EPMC6637769 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-12-01 | GSE95751 | GEO
Project description:Super-enhancers and stretch enhancers (SEs) drive expression of genes that play prominent roles in normal and disease cells, but the functional importance of these clustered enhancer elements is poorly understood, so it is not clear why genes key to cell identity have evolved regulation by such elements. Here we show that super-enhancers consist of functional constituent units that concentrate multiple developmental signaling pathways at key pluripotency genes in embryonic stem cells and confer responsiveness to signaling of their associated genes. Cancer cells frequently acquire SEs at genes that promote tumorigenesis, and we show that these genes are especially sensitive to perturbation of oncogenic signaling pathways. Super-enhancers thus provide a platform for signaling pathways to regulate genes that control cell identity during development and tumorigenesis. ChIP-Seq for H3K27ac and RNA Pol II in mouse embryonic stem cells with CRISPR-deleted enhancers
2014-12-15 | E-GEOD-64188 | biostudies-arrayexpress
Project description:Super-Enhancers Promote Transcriptional Dysregulation in Nasopharyngeal Carcinoma [ChIP-seq]
| PRJNA378260 | ENA
Project description:Super-Enhancers Promote Transcriptional Dysregulation in Nasopharyngeal Carcinoma [RNA-seq]
| PRJNA378262 | ENA
Project description:Super-enhancers are large clusters of transcriptional enhancers that drive expression of genes that control and define cell identity. Improved understanding of the roles super-enhancers play in biology would be afforded by knowing the constellation of factors that constitute these domains and by identifying super-enhancers across the spectrum of human cell types. We describe here the population of transcription factors, cofactors, chromatin regulators and core transcription apparatus that occupy super-enhancers in embryonic stem cells (ESCs) and evidence that super-enhancers are highly transcribed. We then use epigenomic data to produce a catalogue of super-enhancers in a broad range of human cell types. These super-enhancer domains are associated with genes encoding master transcription factors and other components that play important roles in the biology of these cells. Interestingly, sequence variation associated with a broad spectrum of diseases is especially enriched in the super-enhancers of disease-relevant cell types. Furthermore, we find that cancer cells generate super-enhancers at oncogenes and other genes that play important roles in tumor pathogenesis. We discuss these insights and their implications for future study of human health and disease. ChIP-Seq for transcription factors in mouse embryonic stem cells and H3K27ac in Jurkat T-ALL cell line RNA-Seq for mouse embryonic stem cells
2013-10-23 | E-GEOD-51522 | biostudies-arrayexpress
Project description:Using GRO-Seq, we find extensive regulation of enhancer RNAs (eRNA) within super-enhancers in response to lipopolysaccharide treatment in macrophages. Both activation and repression of gene expression are associated with super-enhancers and eRNA transcription dynamics. Co-treatment of LPS and the anti-inflammatory drug dexamethasone targeted specific super-enhancers by attenuating their eRNA expression, leading to reduced expression of key inflammatory genes. We propose that super-enhancers function as molecular rheostats integrating the binding profiles of key regulators to produce dynamic profiles of gene expression. Nascent transcriptome (GRO-Seq) analysis over a time course (0, 20, 60, 180 min) of Lipopolisaccharide and Dexamethasone signaling in mouse bone marrow-derived macrophages.
2014-12-25 | E-GEOD-60857 | biostudies-arrayexpress
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