Press release
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 Published: April 7, 2016 DOI:10.1371/journal.pgen.1005893
Press Release (Only in Japanese)
A large number of variants associated with human complex diseases have been discovered by genome-wide association studies (GWASs). These discoveries have been anticipated to be translated into the definitive understanding of disease pathogeneses; however, functional characterization of the disease-associated SNPs remains a formidable challenge. Here we explored regulatory mechanism of a variant on chromosome 9p21 associated with endometriosis, a common gynecological disorder. By scrutinizing linkage disequilibrium structure and DNase I hypersensitive sites across the risk locus, we prioritized rs17761446 as a candidate causal variant. The results of our “allele-specific” functional genomic approaches sheds light on regulatory mechanisms underlying 9p21 endometriosis risk locus, in which preferential bindings of TCF7L2 and its coactivator EP300 to the protective G allele of rs17761446 lead to stronger chromatin interaction with the promoter of ANRIL, which in turn activate transcription of the non-coding RNA. Motivated by the fact that TCF7L2 was a key transcription factor of Wnt signaling pathway, we postulated that the induction of Wnt signaling activated expression levels of ANRIL and cell cycle inhibitors, CDKN2A/2B. Functional genomics on common disease will unlock functional aspect of genotype-phenotype correlations in the post-GWAS stage.
Regulatory mechanisms underlying 9p21 endometriosis risk locus. Preferential bindings of TCF7L2 and its coactivator EP300 to the protective G allele of rs17761446 lead to stronger chromatin interaction with the promoter of ANRIL, which in turn activate transcription of the non-coding RNA.