Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus

Hirofumi Nakaoka, Aishwarya Gurumurthy, Takahide Hayano, Somayeh Ahmadloo, Waleed H Omer, Kosuke Yoshihara, Akihito Yamamoto, Keisuke Kurose, Takayuki Enomoto, Shigeo Akira, Kazuyoshi Hosomichi, Ituro Inoue
PLoS genetics · 2016 · vol. 12(4) , pp. e1005893 · doi:10.1371/journal.pgen.1005893 · PMID:27055116 · W2326815424
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

This study identified that the protective G allele of rs17761446 at the 9p21 endometriosis risk locus interacts more strongly with the ANRIL promoter, increasing ANRIL expression through enhanced transcription factor binding and chromatin accessibility.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 ⓘ

Nakaoka and colleagues investigated the functional mechanism of an endometriosis-associated 9p21 locus by re-sequencing a 1.29 Mb interval around the reported GWAS SNPs in 48 Japanese individuals and integrating these variants with ENCODE DNase-seq data to prioritize candidate causal variants on DNase I hypersensitive sites. They identified rs17761446 (in perfect linkage disequilibrium with rs10965235) and found that the protective G allele more strongly promotes long-range chromatin interaction with the ANRIL promoter, alongside preferential binding of TCF7L2 and EP300, increased H3K27 acetylation and RNA polymerase II activity, and higher ANRIL expression in allele-specific analyses of eutopic endometrial tissues and endometrial carcinoma cell lines; a key limitation is that many loci were not distinguishable due to perfect linkage disequilibrium among strongly correlated variants. This paper is centrally about endometriosis — it dissects allele-specific regulation of the ANRIL risk locus at chromosome 9p21 as a mechanism underlying endometriosis susceptibility.

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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.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Allelic Imbalance Chromatin Chromosomes, Human, Pair 9 Endometriosis RNA, Long Noncoding Cell Line, Tumor Chromatin E1A-Associated p300 Protein E1A-Associated p300 Protein Endometriosis Female Genome-Wide Association Study Haplotypes Humans Polymorphism, Single Nucleotide Promoter Regions, Genetic RNA, Long Noncoding RNA, Long Noncoding Transcription Factor 7-Like 2 Protein Transcription Factor 7-Like 2 Protein

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