Searching for novel epigenetic regulators for mammalian sex determination

• Project/Area Number: 18K14676
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 43050:Genome biology-related
• Research Institution: Osaka University (2019); The University of Tokushima (2018)
• Principal Investigator: Kuroki Shunsuke 大阪大学, 生命機能研究科, 准教授 (50735793)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 性決定 / エピゲノム

Outline of Final Research Achievements

It has been well known that mammalian sex-determination is made by the sex chromosome system XX (female)/XY (male). On the other hand, the involvement of epigenome in sex determination was not well understood. Recently, we have shown that histone methylation-regulating enzymes Jmjd1a and GLP/G9a contribute to sex determination. However, the whole epigenomic control system that governs sex determination is not yet clear. In this study, we searched for novel epigenetic factors that control the sex-determination. As a result, we have found that histone demethylase Jmdj1b plays a complementary role to Jmjd1a for the expression of sex-determining gene Sry.

Academic Significance and Societal Importance of the Research Achievements

ヒトの性分化疾患（DSD, Disorders of Sex Development）は性の決定・分化が正しく進行しない場合に発症する病気である。DSDの半数以上の症例でその原因は未だ不明である。本研究によって進展したエピゲノムを介した性決定の分子基盤の知見が、DSD発症の新たな原因解明に繋がることが期待される。

Research Products

• [Journal Article] Interferon-γ induces the cell surface exposure of phosphatidylserine by activating the protein MLKL in the absence of caspase-8 activity (2019)
  • Author(s): Chen Jiancheng、Kuroki Shunsuke、Someda Masataka、Yonehara Shin
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 32 Pages: 11994-12006
  • DOI: 10.1074/jbc.ra118.007161
  • Peer Reviewed
• [Journal Article] TET2 catalyzes active DNA demethylation of the Sry promoter and enhances its expression. (2019)
  • Author(s): Okashita N, Kuroki S, Maeda R, *Tachibana M.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 13462-13462
  • DOI: 10.1038/s41598-019-50058-7
  • Peer Reviewed / Open Access
• [Journal Article] Caspase-8, receptor-interacting protein kinase 1 (RIPK1), and RIPK3 regulate retinoic acid-induced cell differentiation and necroptosis. (2019)
  • Author(s): Someda M, Kuroki S, Miyachi H, Tachibana M, *Yonehara S.
  • Journal Title: Cell Death Differ. Volume: - Issue: 5 Pages: 1539-1553
  • DOI: 10.1038/s41418-019-0434-2
  • Peer Reviewed / Open Access
• [Journal Article] Combined loss of JMJD1A and JMJD1B reveals critical roles for H3K9 demethylation in the maintenance of embryonic stem cells and early embryogenesis. (2018)
  • Author(s): Kuroki, S., Nakai, Y., Maeda, R., Okashita, N., Akiyoshi, M., Yamaguchi, Y., Kitano, S., Miyachi, H., Nakato, R., Ichiyanagi, K., Shirahige, K., Kimura, H., Shinkai, Y., and Tachibana, M.
  • Journal Title: Stem Cell Rep. Volume: 10 Issue: 4 Pages: 1340-1354
  • DOI: 10.1016/j.stemcr.2018.02.002
  • NAID: 120006463740
  • Peer Reviewed / Open Access
• [Journal Article] FGF2 Has Distinct Molecular Functions from GDNF in the Mouse Germline Niche (2018)
  • Author(s): Masaki Kaito、Sakai Mizuki、Kuroki Shunsuke、Jo Jun-Ichiro、Hoshina Kazuo、Fujimori Yuki、Oka Kenji、Amano Toshiyasu、Yamanaka Takahiro、Tachibana Makoto、Tabata Yasuhiko、Shiozawa Tanri、Ishizuka Osamu、Hochi Shinichi、Takashima Seiji
  • Journal Title: Stem Cell Reports Volume: 10 Issue: 6 Pages: 1-11
  • DOI: 10.1016/j.stemcr.2018.03.016
  • NAID: 120007037475
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic regulation of mammalian sex determination (2017)
  • Author(s): Kuroki S and *Tachibana M
  • Journal Title: Mol Cell Endocrinol Volume: pii: S0303-7207 Pages: 1-8
  • DOI: 10.1016/j.mce.2017.12.006
  • NAID: 130005129692
  • Peer Reviewed
• [Presentation] H3K9 Demethylases Jmjd1a and Jmjd1b Control Prospermatogonia to Spermatogonia Transition in Mouse Germline (2019)
  • Author(s): 黒木俊介
  • Organizer: 新学術領域「性スペクトラム-連続する表現型としての雌雄」第3回領域会議
• [Presentation] ヒストンH3K9脱メチル化による生殖細胞の分化と制御 (2019)
  • Author(s): 黒木俊介
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] H3K9脱メチル化酵素による雄性生殖細胞の発生制御 (2018)
  • Author(s): 黒木 俊介
  • Organizer: 新学術領域研究 「性スペクトラム-連続する表現型としての雌雄」 第1回 若手研究会
• [Presentation] H3K9脱メチル化による雄性生殖細胞の発生制御 (2018)
  • Author(s): 黒木 俊介
  • Organizer: 新学術領域「性スペクトラム-連続する表現型としての雌雄」第2回 領域会議
• [Presentation] 後天的ゲノム修飾による性決定プログラム分子基盤の解明 (2018)
  • Author(s): 黒木 俊介
  • Organizer: 第121回 日本小児科学会学術集会