Post-GWAS analysis of endometriosis: exploration of transcriptional regulation through chromatin interaction

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08688
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human genetics
• Research Institution: National Institute of Genetics
• Principal Investigator: Nakaoka Hirofumi 国立遺伝学研究所, ゲノム・進化研究系, 助教 (70611193)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 子宮内膜症 / 正常子宮内膜 / 転写制御 / 体細胞変異 / がん関連遺伝子

Outline of Final Research Achievements

We developed a novel 3C-based approach to detect allele-specific chromatin interactions. 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. Furthermore, we investigated regulatory mechanisms underlying the other endometriosis associated loci.
We demonstrated that somatic mutations on cancer-associated genes such as PIK3CA and KRAS were prevalent in epithelial cells in ovarian endometriosis and normal uterine endometrium. Finally, we conducted single endometrial gland RNA-sequencing to evaluate gene expression difference according to somatic mutation status.

Free Research Field

medical genomics

Academic Significance and Societal Importance of the Research Achievements

子宮内膜症は生殖年齢にある女性の約10%に認められる疾患であるが、発症原因は未だ不明である。我々の研究成果は生殖細胞系列の遺伝的多型と子宮内膜症への感受性に関わる転写制御メカニズムを明らかにした。また、子宮内膜における体細胞変異プロファイリングから、子宮内膜が月経血逆流を介して卵巣に生着・増殖する過程で、KRASなど癌関連遺伝子変異を有する腺上皮細胞が生存に有利となり、クローナルに増殖した結果、子宮内膜症発症に繋がったことを示した。生殖細胞系列および体細胞の両面から子宮内膜症発症機序を解明する研究基盤を作ることができた。