Dataset Information

Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression.

ABSTRACT: Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610?kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586?kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30?bp insertion/deletion (indel) variant that was significantly associated with pancreatic cancer risk (rs386772267, P?=?2.30?×?10-11, OR?=?1.22, 95% CI 1.15-1.28) and highly correlated to rs9543325 (r2?=?0.97 in the 1000 Genomes EUR population). This indel was the most significant cis-eQTL variant in a set of 222 histologically normal pancreatic tissue samples (??=?0.26, P?=?0.004), with the insertion (risk-increasing) allele associated with reduced DIS3 expression. DIS3 encodes a catalytic subunit of the nuclear RNA exosome complex that mediates RNA processing and decay, and is mutated in several cancers. Chromosome conformation capture revealed a long range (570 kb) physical interaction between a sub-region of the risk locus, containing rs386772267, and a region ?6?kb upstream of DIS3 Finally, repressor regulatory activity and allele-specific protein binding by transcription factors of the TCF/LEF family were observed for the risk-increasing allele of rs386772267, indicating that expression regulation at this risk locus may be influenced by the Wnt signaling pathway. In conclusion, we have identified a putative functional indel variant at chr13q22.1 that associates with decreased DIS3 expression in carriers of pancreatic cancer risk-increasing alleles, and could therefore affect nuclear RNA processing and/or decay.

SUBMITTER: Hoskins JW

PROVIDER: S-EPMC5815622 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression.

Hoskins Jason W JW Ibrahim Abdisamad A Emmanuel Mickey A MA Manmiller Sarah M SM Wu Yinglun Y O'Neill Maura M Jia Jinping J Collins Irene I Zhang Mingfeng M Thomas Janelle V JV Rost Lauren M LM Das Sudipto S Parikh Hemang H Haake Jefferson M JM Matters Gail L GL Kurtz Robert C RC Bamlet William R WR Klein Alison A Stolzenberg-Solomon Rachael R Wolpin Brian M BM Yarden Ronit R Wang Zhaoming Z Smith Jill J Olson Sara H SH Andresson Thorkell T Petersen Gloria M GM Amundadottir Laufey T LT

Human molecular genetics 20161101 21

Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586 kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30 bp insertion/deletion (indel) variant that was sign ...[more]

PMID: 28172817

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Project description:BackgroundChromatin contacts are essential for gene-expression regulation; however, obtaining a high-resolution genome-wide chromatin contact map is still prohibitively expensive owing to large genome sizes and the quadratic scale of pairwise data. Chromosome conformation capture (3C)-based methods such as Hi-C have been extensively used to obtain chromatin contacts. However, since the sparsity of these maps increases with an increase in genomic distance between contacts, long-range or trans-chromatin contacts are especially challenging to sample.ResultsHere, we create a high-density reference genome-wide chromatin contact map using a meta-analytic approach. We integrate 3600 human, 6700 mouse, and 500 fly Hi-C experiments to create species-specific meta-Hi-C chromatin contact maps with 304 billion, 193 billion, and 19 billion contacts in respective species. We validate that meta-Hi-C contact maps are uniquely powered to capture functional chromatin contacts in both cis and trans. We find that while individual dataset Hi-C networks are largely unable to predict any long-range coexpression (median 0.54 AUC), meta-Hi-C networks perform comparably in both cis and trans (0.65 AUC vs 0.64 AUC). Similarly, for long-range expression quantitative trait loci (eQTL), meta-Hi-C contacts outperform all individual Hi-C experiments, providing an improvement over the conventionally used linear genomic distance-based association. Assessing between species, we find patterns of chromatin contact conservation in both cis and trans and strong associations with coexpression even in species for which Hi-C data is lacking.ConclusionsWe have generated an integrated chromatin interaction network which complements a large number of methodological and analytic approaches focused on improved specificity or interpretation. This high-depth "super-experiment" is surprisingly powerful in capturing long-range functional relationships of chromatin interactions, which are now able to predict coexpression, eQTLs, and cross-species relationships. The meta-Hi-C networks are available at https://labshare.cshl.edu/shares/gillislab/resource/HiC/ .

Dataset Information

Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression.

Publications

Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression.

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