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

2017 Fiscal Year Final Research Report

• Project/Area Number: 15H02373
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical genome science
• Research Institution: National Institute of Genetics
• Principal Investigator: Inoue Ituro 国立遺伝学研究所, 総合遺伝研究系, 教授 (00192500)
• Co-Investigator(Kenkyū-buntansha): 佐藤 健人 東海大学, 医学部, 准教授 (50235363) ; 細道 一善 金沢大学, 医学系, 准教授 (50420948)
• Co-Investigator(Renkei-kenkyūsha): ENOMOTO Takayuki 新潟大学, 医歯学系, 教授 (90283754) ; AKIRA Shigeo 日本医科大学, 医学部, 教授 (40231849)
• Research Collaborator: NAKAOKA Hirofumi 国立遺伝学研究所, 総合遺伝研究系, 助教 (70611193)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 子宮内膜症 / アレル優位性 / エンハンサー活性 / クロマチン高次構造 / 疾患関連遺伝子

Outline of Final Research Achievements

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 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. The protective allele exhibited preferential binding affinities to TCF7L2 and EP300 by chromatin immunoprecipitation (ChIP) analyses. 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.

Free Research Field

ゲノム医科学