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

• 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
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• 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 / KRAS / PIK3CA / ARID1A / 子宮内膜 / 腺管 / クロマチン相互作用 / ゲノムワイド関連解析 / ポストゲノムワイド関連解析

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.

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。

Research Products

• [Journal Article] Clonal lineage from normal endometrium to ovarian clear cell carcinoma through ovarian endometriosis (2020)
  • Author(s): Suda K, Cruz Diaz LA, Yoshihara K, Nakaoka H, Yachida N, Motoyama T, Inoue I, Enomoto T
  • Journal Title: Cancer Science Volume: in press
  • Peer Reviewed
• [Journal Article] Different mutation profiles between epithelium and stroma in endometriosis and normal endometrium (2019)
  • Author(s): Suda Kazuaki、Nakaoka Hirofumi、Yoshihara Kosuke、Ishiguro Tatsuya、Adachi Sosuke、Kase Hiroaki、Motoyama Teiichi、Inoue Ituro、Enomoto Takayuki
  • Journal Title: Human Reproduction Volume: 34 Issue: 10 Pages: 1899-1905
  • DOI: 10.1093/humrep/dez155
  • Peer Reviewed
• [Journal Article] Concurrent isolated retroperitoneal HGSC and STIC defined by somatic mutation analysis: a case report (2019)
  • Author(s): Suda Kazuaki、Nakaoka Hirofumi、Hata Chihiro、Yahata Natsumi、Isobe Masanori、Kameyama Hitoshi、Wakai Toshifumi、Motoyama Teiichi、Inoue Ituro、Yoshihara Kosuke、Enomoto Takayuki
  • Journal Title: Diagnostic Pathology Volume: 14 Issue: 1 Pages: 17-17
  • DOI: 10.1186/s13000-019-0795-3
  • Peer Reviewed / Open Access
• [Journal Article] Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium (2018)
  • Author(s): Suda Kazuaki、Nakaoka Hirofumi、Yoshihara Kosuke、Ishiguro Tatsuya、Tamura Ryo、Mori Yutaro、Yamawaki Kaoru、Adachi Sosuke、Takahashi Tomoko、Kase Hiroaki、Tanaka Kenichi、Yamamoto Tadashi、Motoyama Teiichi、Inoue Ituro、Enomoto Takayuki
  • Journal Title: Cell Reports Volume: 24 Issue: 7 Pages: 1777-1789
  • DOI: 10.1016/j.celrep.2018.07.037
  • Peer Reviewed / Open Access
• [Journal Article] Novel therapeutic strategy for cervical cancer harboring FGFR3-TACC3 fusions (2018)
  • Author(s): Tamura R, Yoshihara K, Saito T, Ishimura R, Martinez-Ledesma JE, Xin H, Ishiguro T, Mori Y, Yamawaki K, Suda K, Sato S, Itamochi H, Motoyama T, Aoki Y, Okuda S, Casingal CR, Nakaoka H, Inoue I, Verhaak RGW, Komatsu M, Enomoto T.
  • Journal Title: Oncogenesis Volume: 7 Issue: 1 Pages: 4-4
  • DOI: 10.1038/s41389-017-0018-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 子宮内膜症のポストGWAS解析 (2018)
  • Author(s): 中岡博史
  • Journal Title: 別冊BIO Clinica（バイオクリニカ）慢性炎症と疾患 Volume: 第6巻 Pages: 105-111
• [Journal Article] Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses (2017)
  • Author(s): Ito J, Sugimoto R, Nakaoka H, Yamada S, Kimura T, Hayano T, Inoue I.
  • Journal Title: PLOS Genetics Volume: 13 Issue: 7 Pages: e1006883-e1006883
  • DOI: 10.1371/journal.pgen.1006883
  • Peer Reviewed / Open Access
• [Presentation] Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. (2018)
  • Author(s): Nakaoka H, Suda K, Yoshihara K, Enomoto T, Inoue I.
  • Organizer: The American Society of Human Genetics 68th Annual Meeting.
  • Int'l Joint Research