Sperm DNA methylation for a risk of offspring's disorder

• Project/Area Number: 17K17605
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology; General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Kimura Ryuichi 東北大学, 医学系研究科, 助教 (00781759)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 精子エピゲノム / 神経発達障害 / 加齢 / 発生・分化 / 老化 / 発現制御 / 脳神経疾患

Outline of Final Research Achievements

In this study, we clarified the expression of REST / NRSF during the spermatogenesis process, which was unknown until now. Analysis of gene expression data in the germ cell line of the cell fractionated testis shows that REST / NRSF is most expressed in A-type spermatozoa, known as germline stem cells and the expression levels was decreased with progress of spermatogenesis. Furthermore, by creating a knock-in mouse with an epitope tag attached to the C-terminus of endogenous REST / NRSF, we have clarified for the first time the expression and localization of REST / NRSF protein in germ cell line.

Academic Significance and Societal Importance of the Research Achievements

本研究により、雄の生殖細胞系列におけるREST/NRSFの発現と局在が初めてを明らかとなり、加齢より精子DNAメチル化異常が生じる分子機構の一端に迫ることができた。父親の高齢は子どもの自閉スペクトラム障害や統合失調症といった疾患のリスク因子であり、加齢により生じる精子DNAメチル化の変化がその原因の1つである可能性が指摘されている。今後、精子形成におけるREST/NRSFの機能を検討することにより、REST/NRSFによる精子DNAメチル化の制御機構が明らかとなれば、高齢の父親に由来する子孫の疾患リスクを低減するような予防的介入法の開発につながると期待される。

Research Products

• [Journal Article] 自閉スペクトラム症発症リスクとエピジェネティクス (2019)
  • Author(s): 木村龍一、稲田仁、大隅典子
  • Journal Title: 医学のあゆみ Volume: 3 Pages: 180-183
• [Journal Article] Risk of Neurodevelopmental Disease by Paternal Aging: A Possible Infuence of Epigenetic Alteration in Sperm. (2018)
  • Author(s): Kimura, R., Yoshizaki, K. and Osumi, N.
  • Journal Title: Adv. Exp. Med. Biol. Volume: 1012 Pages: 75-81
  • DOI: 10.1007/978-981-10-5526-3_8
  • ISBN: 9789811055256, 9789811055263
  • Peer Reviewed
• [Presentation] Paternal aging affects gene expression of offspring’s brain possibly via epigenetic mechanism involving a transcriptional repressor REST (2018)
  • Author(s): 大隅典子
  • Organizer: ISDN2018
  • Int'l Joint Research
• [Presentation] Paternal ageing affects phenotypes of mice progeny possibly through epigenetic alteration in sperm (2018)
  • Author(s): 木村龍一
  • Organizer: 第41回日本神経科学大会
  • Invited
• [Presentation] Paternal aging affects offspring’s behavior and gene expression possibly through transmission of hypomethylated DNA regions in NRSF/REST binding sites (2018)
  • Author(s): 木村龍一
  • Organizer: Neuroscience 2018
  • Int'l Joint Research
• [Presentation] Paternal ageing affects phenotypes of mice progeny possibly through epigenetic alteration in sperm (2018)
  • Author(s): Kimura R., Yoshizaki K., Koike T., Oki S., Aoki N., Mochizuki K., Kobayashi H., Kikkawa T., Inada H., Matsui Y., Kono T., Osumi N.
  • Organizer: 第41回日本神経科学大会
  • Invited
• [Presentation] 高齢の精子にみられるDNAメチル化異常と子孫の表現型異常との関連 (2017)
  • Author(s): 木村龍一、吉崎嘉一、小池佐、沖真弥、青木七菜、望月健太郎、小林久人、吉川貴子、稲田仁、松居靖久、河野友宏、大隅典子
  • Organizer: 第40回日本神経科学大会
• [Presentation] Paternal age affects offspring’s behavior possibly via sperm epigenetic alteration established by a transcriptional repressor REST (2017)
  • Author(s): Kimura R., Yoshizaki K., Koike T., Oki S., Aoki N., Mochizuki K., Kobayashi H., Kikkawa T., Inada H., Matsui Y., Kono T., Osumi N.
  • Organizer: The International Research Symposium on Regulation of Germ Cell Development in vivo and in vitro
  • Int'l Joint Research
• [Presentation] Trans-generational transmission of ASD-like phenotypes possibly via sperm epigenetic alteration caused by paternal age (2017)
  • Author(s): Kimura R., Yoshizaki K., Koike T., Oki S., Aoki N., Mochizuki K., Kobayashi H., Kikkawa T., Inada H., Matsui Y., Kono T., Osumi N.
  • Organizer: 国際自閉症カンファレンス東京2017
  • Int'l Joint Research