Abstract
The identification of target genes at genome-wide association study (GWAS) loci is a major obstacle for GWAS follow-up. To identify candidate target genes at the 16 known endometrial cancer GWAS risk loci, we performed HiChIP chromatin looping analysis of endometrial cell lines. To enrich for enhancer–promoter interactions, a mechanism through which GWAS variation may target genes, we captured chromatin loops associated with H3K27Ac histone, characteristic of promoters and enhancers. Analysis of HiChIP loops contacting promoters revealed enrichment for endometrial cancer GWAS heritability and intersection with endometrial cancer risk variation identified 103 HiChIP target genes at 13 risk loci. Expression of four HiChIP target genes (SNX11, SRP14, HOXB2 and BCL11A) was associated with risk variation, providing further evidence for their targeting. Network analysis functionally prioritized a set of proteins that interact with those encoded by HiChIP target genes, and this set was enriched for pan-cancer and endometrial cancer drivers. Lastly, HiChIP target genes and prioritized interacting proteins were over-represented in pathways related to endometrial cancer development. In summary, we have generated the first global chromatin looping data from normal and tumoral endometrial cells, enabling analysis of all known endometrial cancer risk loci and identifying biologically relevant candidate target genes.
Highlights
To date, 16 loci have been found to robustly associate with endometrial cancer risk by genome-wide association studies (GWAS) [1,2,3]
We previously found that a majority of endometrial cancer risk credible variants (CVs) from ten recently discovered GWAS loci were coincident with promoteror enhancer-associated epigenetic features in relevant cell lines or tissues [1]
The follow-up of GWAS is challenging because the target genes of CVs are generally not obvious; as CVs located in enhancers can regulate promoter activity over long distances through chromatin looping [2,8,9,10,11] and enhancers do not necessarily loop to the nearest gene [12]
Summary
16 loci have been found to robustly associate with endometrial cancer risk by genome-wide association studies (GWAS) [1,2,3]. As for other GWAS, the vast majority of credible variants (CVs; i.e., the lead variant and other correlated variants) at these loci are non-coding and likely mediate their effects through gene regulation (as reviewed in [4]). We previously found that a majority of endometrial cancer risk CVs from ten recently discovered GWAS loci were coincident with promoteror enhancer-associated epigenetic features in relevant cell lines or tissues [1]. The overlap between CVs and these elements was significantly greater for features observed in endometrial cancer cell lines after stimulation with estrogen [1], one of the most established risk factors for endometrial cancer [5,6,7].
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