Analysis of the interaction between embryo and uterus during the preimplantation period based on epigenome

• Project/Area Number: 17H06640
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Obstetrics and gynecology
• Research Institution: The University of Tokyo
• Principal Investigator: Haraguchi Hirofumi 東京大学, 医学部附属病院, 助教 (50804506)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 妊娠・着床 / エピゲノム

Outline of Final Research Achievements

Since changes of DNA methylation in embryos just before implantation are unknown, we investigated DNA methylation of mouse embryos between before and after activation. Many of the genes whose expression has changed have differences in DNA methylation. This result was suggested that expression changes due to methylation during preimplantation period. In the analysis of mouse uterus, implantation site was about three times as many as the number of genes whose expression was changed compared to non-implantation site. It was shown that implantation induced large gene expression changes in uterus. Progestin is used for infertility treatment and contraception. When we administered high doses of progestin before implantation, implantation failure was observed, and LIF, which is essential for implantation, was reduced. Implantation failure of this model was improved by administration of LIF. These results indicate that excessive progestin may reduce LIF in the uterus and inhibit implantation.

Academic Significance and Societal Importance of the Research Achievements

着床機構の解明は生命科学の研究対象として興味深いだけではなく、臨床生殖医学の見地からも重要である。今回の成果は、未だ詳細がわかっていない着床機構の解明につながる可能性がある。また、少子化が叫ばれている近年の社会情勢は不妊症治療が必要となっており、今回の成果が、不妊治療の更なる発展や、新規の避妊法の開発、生殖医療における卵巣ホルモンの適正使用の向上につながる可能性があると考えられる。

Research Products

• [Journal Article] Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditining oocyte quality. (2019)
  • Author(s): Haraguchi H, Hirota Y, Saito-Fujita T, Tanaka T, Shimizu-Hirota R, Harada M, Akaeda S, Hiraoka T, Matsuo M, Matsumoto L, Hirata T, Koga K, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: FASEB J Volume: 33 Pages: 2610-2620
  • DOI: 10.1096/fj.201801401r
  • Peer Reviewed / Open Access
• [Journal Article] HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment (2018)
  • Author(s): Matsumoto L, Hirota Y, Saito-Fujita T, Takeda N, Tanaka T, Hiraoka T, Akaeda S, Fujita H, Shimizu-Hirota R, Igaue S, Matsuo M, Haraguchi H, Saito-Kanatani M, Fujii T, Osuga Y.
  • Journal Title: J Clin Invest Volume: 128 Pages: 3186-3197
  • DOI: 10.1172/jci98931
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] F4/80+ macrophages contribute to clearance of senescent cells in the mouse postpartum uterus. (2017)
  • Author(s): Egashira M, Hirota Y, Shimizu-Hirota R, Saito-Fujita T, Haraguchi H, Matsumoto L, Matsuo M, Hiraoka T, Tanaka T, Akaeda S, Takehisa C, Saito-Kanatani M, Maeda K, Fujii T, Osuga Y.
  • Journal Title: Endocrinology Volume: 印刷中 Pages: 2344-2353
  • DOI: 10.1210/en.2016-1886
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Mdm2-p53 axis is a key machinery of ovulation. (2018)
  • Author(s): 原口広史，廣田泰，藤田知子，松本玲央奈，松尾光徳，平岡毅大，赤枝俊，田中智基，大須賀穣，藤井知行
  • Organizer: 第70回日本産科婦人科学会学術講演会
• [Presentation] Levonorgestrel Inhibits Embryo Implantation by Downregulation of Uterine LIF Expression (2018)
  • Author(s): Mitsunori Matsuo, Yasushi Hirota, Tomoko Saito-Fujita, Hirofumi Haraguchi, Shota Igaue, Leona Matsumoto, Takehiro Hiraoka, Shun Akaeda, Tomoki Tanaka, Tomoyuki Fujii, Yutaka Osuga. 
  • Organizer: Society for Reproductive Investigation, 65th Annual Scientific Meeting, Endometrium Satellite Meeting
  • Int'l Joint Research
• [Presentation] Mdm2-p53 axis is a key machinery of ovulation. (2018)
  • Author(s): 原口広史 廣田泰 藤田知子 松本玲央奈 松尾光徳 平岡毅大 赤枝俊 田中智基 大須賀穣 藤井知行
  • Organizer: 第70回日本産科婦人科学会学術講演会
• [Presentation] Tumor suppressor p53 impairs cumulus cell-oocyte complex expansion and ovulation (2017)
  • Author(s): 原口広史 廣田泰 藤田知子 松本玲央奈松尾光徳 平岡毅大 赤枝俊田中智基 大須賀穣 藤井知行
  • Organizer: 第69回日本産科婦人科学会学術講演会
• [Presentation] Global gene expression profile in the luminal epithelium of the mouse uterus during embryo attachment. (2017)
  • Author(s): 伊賀上翔太 廣田泰 藤田知子 原口広史松本玲於奈 松尾光徳平岡毅大 田中智基 赤枝俊 大須賀穣 藤井知行
  • Organizer: 第69回日本産科婦人科学会学術講演会
• [Presentation] DNA methylation and its transcriptional regulation of pre-implantation mouse blastocyst in the process of blastocyst activation (2017)
  • Author(s): 平塚大輝 廣田泰 原口広史 藤田知子 松本玲央奈 松尾光徳 平岡毅大 赤枝俊 田中智基 大須賀穣 藤井知行
  • Organizer: 第69回日本産科婦人科学会学術講演会
• [Presentation] 卵巣のMouse double minute 2 homolog（Mdm2）欠損による過剰なp53はsteroidogenic factor 1（SF1）を誘導し排卵障害を引き起こす (2017)
  • Author(s): 原口広史 廣田泰 藤田知子 松本玲央奈 松尾光徳 平岡毅大 赤枝俊 田中智基 大須賀穣 藤井知行
  • Organizer: 第62回日本生殖医学会学術講演会