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A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer [HiC]

ABSTRACT: A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer [HiC]

PROVIDER: PRJNA801701 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17813575_1.fastq.gz	Fastqsanger.gz
	SRR17813575_2.fastq.gz	Fastqsanger.gz
	SRR17813576_1.fastq.gz	Fastqsanger.gz
	SRR17813576_2.fastq.gz	Fastqsanger.gz
	SRR17813577_1.fastq.gz	Fastqsanger.gz

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A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer [HiC]

Project description:Ovarian cancer is one of the deadliest cancers among women worldwide and is the leading cause of gynecologic-related cancer deaths in the U.S. Enhancers are often repurposed by the tumor cells for the regulation of genes that allow tumor cells to become more aggressive and resistant to therapy. Recent evidence suggests that exploiting transcriptional dependence by targeting oncogenic super-enhancers may be a viable therapeutic avenue. To this end, we leveraged genomic data such as H3K27ac, BRD4, and copy number information to identify putatively oncogenic super-enhancers. We found that copy number amplification of these super-enhancers is predictive of clinical outcome and that the targets genes associated to the copy number events via chromatin eQTL analysis are involved in numerous oncogenic processes. To systematically probe the functions these super-enhancers we designed a CRISPR interference screen (dCas9-KRAB) so specifically inhibit each super-enhancer and measure the consequences on gene expression via RNA-seq. These results show pervasive gene expression changes that underlie the biology of ovarian cancer. Finally, we select two salient super-enhancers for further analysis. CRISPR-based deletion of these two super-enhancers results in in dramatic changes in gene expression and decreased cell proliferation of ovarian cancer cells. Taken together these analyses highlight the importance of BRD4-bound and copy number amplified super-enhancers in ovarian cancer oncogenic regulation.

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Project description:A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer [ChIP-seq]

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A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer.

Project description:The human genome contains regulatory elements, such as enhancers, that are often rewired by cancer cells for the activation of genes that promote tumorigenesis and resistance to therapy. This is especially true for cancers that have little or no known driver mutations within protein coding genes, such as ovarian cancer. Herein, we utilize an integrated set of genomic and epigenomic datasets to identify clinically relevant super-enhancers that are preferentially amplified in ovarian cancer patients. We systematically probe the top 86 super-enhancers, using CRISPR-interference and CRISPR-deletion assays coupled to RNA-sequencing, to nominate two salient super-enhancers that drive proliferation and migration of cancer cells. Utilizing Hi-C, we construct chromatin interaction maps that enable the annotation of direct target genes for these super-enhancers and confirm their activity specifically within the cancer cell compartment of human tumors using single-cell genomics data. Together, our multi-omic approach examines a number of fundamental questions about how regulatory information encoded into super-enhancers drives gene expression networks that underlie the biology of ovarian cancer.

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