Abstract
Enhancers are short regulatory regions (50-1500 bp) of DNA that control the tissue-specific activation of gene expression by long distance interaction with targeting gene regions. Recently, genome-wide identification of enhancers in diverse tissues and cell lines was achieved using high-throughput sequencing. Enhancers have been associated with malfunctions in cancer development resulting from point mutations in regulatory regions. However, the potential impact of copy number variations (CNVs) on enhancer regions is unknown. To learn more about the relationship between enhancers and cancer, we integrated the CNVs data on enhancers and explored their targeting gene expression pattern in high-grade ovarian cancer. Using human enhancer-gene interaction data with 13,691 interaction pairs between 7,905 enhancers and 5,297 targeting genes, we found that the 2,910 copy number gain events of enhancer are significantly correlated with the up-regulation of targeting genes. We further identified that a number of highly mutated super-enhancers, with concordant gene expression change on their targeting genes. We also identified 18 targeting genes by super-enhancers with prognostic significance for ovarian cancer, such as the tumour suppressor CDKN1B. We are the first to report that abundant copy number variations on enhancers could change the expression of their targeting genes which would be valuable for the design of enhancer-based cancer treatment strategy.
Highlights
To establish and maintain specific physiological states in different developmental stages and cell types, gene expression is highly regulated by thousands of transcription factors (TFs), cofactors and chromatin regulators [1]
By further incorporating the gene expression of enhancer targeting genes, we could check whether the copy number variation (CNV) on enhancer have effects on the expression change of targeting genes
To survey the role of enhancers in ovarian cancer, we focused on the CNVs on enhancer regions and constructed a computational framework with extensive data integration (Figure 1, see Methods)
Summary
To establish and maintain specific physiological states in different developmental stages and cell types, gene expression is highly regulated by thousands of transcription factors (TFs), cofactors and chromatin regulators [1]. The TFs and cofactors are often binding in specific genomic regions that include promoters and enhancers. Compared to the proximal promoters for gene regulation, enhancers are often physically located up to 1Mbp away from the target genes [2]. These gene-distal regulatory elements can be upstream or downstream from the transcription starting site and either in the forward or reverse strand. The roles of enhancer in ovarian cancers have been reported in only one recent publication and at single gene level [5]
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