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Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus.
- Source :
-
PLoS genetics [PLoS Genet] 2016 Apr 07; Vol. 12 (4), pp. e1005893. Date of Electronic Publication: 2016 Apr 07 (Print Publication: 2016). - Publication Year :
- 2016
-
Abstract
- Genome-wide association studies (GWASs) have discovered numerous single nucleotide polymorphisms (SNPs) associated with human complex disorders. However, functional characterization of the disease-associated SNPs remains a formidable challenge. Here we explored regulatory mechanism of a SNP on chromosome 9p21 associated with endometriosis by leveraging "allele-specific" functional genomic approaches. By re-sequencing 1.29 Mb of 9p21 region and scrutinizing DNase-seq data from the ENCODE project, we prioritized rs17761446 as a candidate functional variant that was in perfect linkage disequilibrium with the original GWAS SNP (rs10965235) and located on DNase I hypersensitive site. Chromosome conformation capture followed by high-throughput sequencing revealed that the protective G allele of rs17761446 exerted stronger chromatin interaction with ANRIL promoter. We demonstrated that the protective allele exhibited preferential binding affinities to TCF7L2 and EP300 by bioinformatics and chromatin immunoprecipitation (ChIP) analyses. ChIP assays for histone H3 lysine 27 acetylation and RNA polymerase II reinforced the enhancer activity of the SNP site. The allele specific expression analysis for eutopic endometrial tissues and endometrial carcinoma cell lines showed that rs17761446 was a cis-regulatory variant where G allele was associated with increased ANRIL expression. Our work illuminates the allelic imbalances in a series of transcriptional regulation from factor binding to gene expression mediated by chromatin interaction underlie the molecular mechanism of 9p21 endometriosis risk locus. Functional genomics on common disease will unlock functional aspect of genotype-phenotype correlations in the post-GWAS stage.
- Subjects :
- Cell Line, Tumor
E1A-Associated p300 Protein metabolism
Female
Genome-Wide Association Study
Haplotypes
Humans
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
RNA, Long Noncoding metabolism
Transcription Factor 7-Like 2 Protein metabolism
Allelic Imbalance
Chromatin genetics
Chromosomes, Human, Pair 9
Endometriosis genetics
RNA, Long Noncoding genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7404
- Volume :
- 12
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PLoS genetics
- Publication Type :
- Academic Journal
- Accession number :
- 27055116
- Full Text :
- https://doi.org/10.1371/journal.pgen.1005893