Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus.
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 chrom...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-04-01
|
| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC4824487?pdf=render |
| _version_ | 1811279363584294912 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Hirofumi Nakaoka |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T00:53:16Z |
| format | Article |
| id | doaj.art-8f2775bce2ca4aae90a5bc0495a07610 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-13T00:53:16Z |
| publishDate | 2016-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-8f2775bce2ca4aae90a5bc0495a076102022-12-22T03:09:47ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042016-04-01124e100589310.1371/journal.pgen.1005893Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus.Hirofumi NakaokaAishwarya GurumurthyTakahide HayanoSomayeh AhmadlooWaleed H OmerKosuke YoshiharaAkihito YamamotoKeisuke KuroseTakayuki EnomotoShigeo AkiraKazuyoshi HosomichiIturo InoueGenome-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.http://europepmc.org/articles/PMC4824487?pdf=render |
| spellingShingle | 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 Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus. PLoS Genetics |
| title | Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus. |
| title_full | Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus. |
| title_fullStr | Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus. |
| title_full_unstemmed | Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus. |
| title_short | Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus. |
| title_sort | allelic imbalance in regulation of anril through chromatin interaction at 9p21 endometriosis risk locus |
| url | http://europepmc.org/articles/PMC4824487?pdf=render |
| work_keys_str_mv | AT hirofuminakaoka allelicimbalanceinregulationofanrilthroughchromatininteractionat9p21endometriosisrisklocus AT aishwaryagurumurthy allelicimbalanceinregulationofanrilthroughchromatininteractionat9p21endometriosisrisklocus AT takahidehayano allelicimbalanceinregulationofanrilthroughchromatininteractionat9p21endometriosisrisklocus AT somayehahmadloo allelicimbalanceinregulationofanrilthroughchromatininteractionat9p21endometriosisrisklocus AT waleedhomer allelicimbalanceinregulationofanrilthroughchromatininteractionat9p21endometriosisrisklocus AT kosukeyoshihara allelicimbalanceinregulationofanrilthroughchromatininteractionat9p21endometriosisrisklocus AT akihitoyamamoto allelicimbalanceinregulationofanrilthroughchromatininteractionat9p21endometriosisrisklocus AT keisukekurose allelicimbalanceinregulationofanrilthroughchromatininteractionat9p21endometriosisrisklocus AT takayukienomoto allelicimbalanceinregulationofanrilthroughchromatininteractionat9p21endometriosisrisklocus AT shigeoakira allelicimbalanceinregulationofanrilthroughchromatininteractionat9p21endometriosisrisklocus AT kazuyoshihosomichi allelicimbalanceinregulationofanrilthroughchromatininteractionat9p21endometriosisrisklocus AT ituroinoue allelicimbalanceinregulationofanrilthroughchromatininteractionat9p21endometriosisrisklocus |