Sex spectrum of embryonic gonads

• Project Area: Spectrum of the Sex: a continuity of phenotypes between female and male
• Project/Area Number: 17H06424
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University (2018-2021); The University of Tokushima (2017)
• Principal Investigator: Makoto Tachibana 大阪大学, 生命機能研究科, 教授 (80303915)
• Project Period (FY): 2017-06-30 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥212,680,000 (Direct Cost: ¥163,600,000、Indirect Cost: ¥49,080,000); Fiscal Year 2021: ¥38,740,000 (Direct Cost: ¥29,800,000、Indirect Cost: ¥8,940,000); Fiscal Year 2020: ¥38,740,000 (Direct Cost: ¥29,800,000、Indirect Cost: ¥8,940,000); Fiscal Year 2019: ¥38,740,000 (Direct Cost: ¥29,800,000、Indirect Cost: ¥8,940,000); Fiscal Year 2018: ¥38,740,000 (Direct Cost: ¥29,800,000、Indirect Cost: ¥8,940,000); Fiscal Year 2017: ¥57,720,000 (Direct Cost: ¥44,400,000、Indirect Cost: ¥13,320,000)
• Keywords: 性スペクトラム / 性決定 / 生殖腺 / ヘテロクロマチン / 性決定遺伝子 / エピゲノム / ヒストン / メチル化修飾

Outline of Final Research Achievements

We have been conducting research with the goal of redefining sex by regarding males and females as a continuous phenotype. Previous studies have shown that the fetal gonads of genetically mutated mice exhibit a phenotype called "ovotestis," which is a mixture of male and female cells. Our research results revealed that epigenetic regulation by methylation of lysine 9 of histone H3 and DNA contribute to the development of ovotestis.

Academic Significance and Societal Importance of the Research Achievements

ある種の遺伝子変異マウスの生殖腺は、オス型細胞とメス型細胞の混ざりからなる「卵精巣」を形成することが分かっています。私たちは、このようなオスとメスの中間の生殖腺ができる仕組みには、ゲノムの後天的な修飾である「エピゲノム」が深く関わっていることを明らかにしました。すなわち、細胞の核内に存在するヒストンと呼ばれるタンパク質にどの程度のメチル基が付加されるかによって、胎仔の生殖腺のオス化とメス化の度合いが決まることを見いだしました。本研究の成果は、雌雄を「二項対立的なもの」として捉えるべきではなく、「連続する表現型（スペクトラム）」として捉えるべきとの考え方を支持します。

Research Products

• [Int'l Joint Research] クイーンズランド大学(オーストラリア)
• [Int'l Joint Research] カリフォルニア大学デービス校(米国)
• [Int'l Joint Research] クイーンズランド大学(オーストラリア)
• [Int'l Joint Research] Qeensland University(オーストラリア)
• [Int'l Joint Research] The University of Blitish Columbia(カナダ)
• [Int'l Joint Research] IGMM(フランス)
• [Journal Article] HP1 maintains protein stability of H3K9 methyltransferases and demethylases (2022)
  • Author(s): Ryo Maeda, Makoto Tachibana
  • Journal Title: EMBO Reports Volume: 23 Issue: 4
  • DOI: 10.15252/embr.202153581
  • Peer Reviewed
• [Journal Article] マウス性決定遺伝子Sryの「隠れたエキソン」の発見 (2022)
  • Author(s): 立花誠
  • Journal Title: ファルマシア Volume: 58 Pages: 34-38
  • NAID: 130008138918
• [Journal Article] Dynamic erectile responses of a novel penile organ model utilizing TPEM. (2021)
  • Author(s): Hashimoto D, Hirashima T, Yamamura H, Kataoka T, Fujimoto K, Hyuga T, Yoshiki A, Kimura K, Kuroki S, Tachibana M, Suzuki K, Yamamoto N, Morioka S, Sasaki T, Yamada G.
  • Journal Title: Biol Reprod. Volume: in press Issue: 4 Pages: 875-886
  • DOI: 10.1093/biolre/ioab011
  • Peer Reviewed / Open Access
• [Journal Article] Meiosis-specific ZFP541 repressor complex promotes developmental progression of meiotic prophase towards completion during mouse spermatogenesis (2021)
  • Author(s): Horisawa-Takada Yuki et al.
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 3184-3184
  • DOI: 10.1038/s41467-021-23378-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 性決定遺伝子の全貌-マウスSryにおける“隠れエキソン”の発見- (2021)
  • Author(s): 宮脇慎吾、立花誠
  • Journal Title: 医学のあゆみ Volume: 278 Pages: 1132-1133
• [Journal Article] マウスの性決定遺伝子Sryにおける「隠れエキソン」の発見と、それがコードする真の性決定因子SRY-Tの発見 (2021)
  • Author(s): 宮脇慎吾、立花誠
  • Journal Title: 実験医学 Volume: 39 Pages: 571-574
• [Journal Article] Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis (2021)
  • Author(s): Takuma Nakatsuka, Keisuke Tateishi*, Hiroyuki Kato, Hiroaki Fujiwara, Keisuke Yamamoto, Yotaro Kudo, Hayato Nakagawa, Yasuo Tanaka, Hideaki Ijichi, Tsuneo Ikenoue, Takeaki Ishizawa, Kiyoshi Hasegawa, Makoto Tachibana, Yoichi Shinkai, Kazuhiko Koike
  • Journal Title: Cell Death and Disease Volume: 12 Issue: 1 Pages: 99111-99111
  • DOI: 10.1038/s41419-020-03381-1
  • Peer Reviewed / Open Access
• [Journal Article] G9a is involved in the regulation of cranial bone formation through activation of Runx2 function during development (2020)
  • Author(s): Ideno Hisashi、Nakashima Kazuhisa、Komatsu Koichiro、Araki Ryoko、Abe Masumi、Arai Yoshinori、Kimura Hiroshi、Shinkai Yoichi、Tachibana Makoto、Nifuji Akira
  • Journal Title: Bone Volume: 137 Pages: 115332-115332
  • DOI: 10.1016/j.bone.2020.115332
  • Peer Reviewed / Open Access
• [Journal Article] H3K9 Demethylases JMJD1A and JMJD1B Control Prospermatogonia to Spermatogonia Transition in Mouse Germline (2020)
  • Author(s): Kuroki Shunsuke、Maeda Ryo、Yano Masashi、Kitano Satsuki、Miyachi Hitoshi、Fukuda Mikiko、Shinkai Yoichi、Tachibana Makoto
  • Journal Title: Stem Cell Reports Volume: 15 Issue: 2 Pages: 424-438
  • DOI: 10.1016/j.stemcr.2020.06.013
  • NAID: 120007146093
  • Peer Reviewed / Open Access
• [Journal Article] The mouse Sry locus harbors a cryptic exon that is essential for male sex determination (2020)
  • Author(s): Miyawaki Shingo、Kuroki Shunsuke、Maeda Ryo、Okashita Naoki、Koopman Peter、Tachibana Makoto
  • Journal Title: Science Volume: 370 Issue: 6512 Pages: 121-124
  • DOI: 10.1126/science.abb6430
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deletion of Histone Methyltransferase G9a Suppresses Mutant Kras-driven Pancreatic Carcinogenesis Carcinogenesis (2020)
  • Author(s): Hiroyuki Kato, Keisuke Tateishi*, Hiroaki Fujiwara, Hideaki Ijichi, Keisuke Yamamoto, Takuma Nakatsuka, Miwako Kakiuchi, Makoto Sano, Yotaro Kudo, Yoku Hayakawa, Hayato Nakagawa, Yasuo Tanaka, Motoyuki Otsuka, Yoshihiro Hirata, Makoto Tachibana, Yoichi Shinkai, Kazuhiko Koike
  • Journal Title: Cancer Genomics Proteomics Volume: 17 Issue: 6 Pages: 695705-695705
  • DOI: 10.21873/cgp.20224
  • 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] 遺伝子改変マウスの作成と技術進歩 (2019)
  • Author(s): 宮脇慎吾、立花誠
  • Journal Title: 生産と技術 Volume: 71 Pages: 15-20
• [Journal Article] Role of epigenetic regulation in mammalian sex determination. (2019)
  • Author(s): Shingo Miyawaki, Makoto Tachibana
  • Journal Title: Curr Top Dev Biol. Volume: 134 Pages: 195-221
  • DOI: 10.1016/bs.ctdb.2019.01.008
  • Peer Reviewed
• [Journal Article] Histone H3K9 Methyltransferase G9a in Oocytes Is Essential for Preimplantation Development but Dispensable for CG Methylation Protection. (2019)
  • Author(s): Yeung WKA, Brind’Amour J, Hatano Y, Yamagata K, Feil R, Matthew C. Lorincz MC, Tachibana M, Shinkai Y, Sasaki H*.
  • Journal Title: Cell Rep. Volume: 27 Issue: 1 Pages: 282-293
  • DOI: 10.1016/j.celrep.2019.03.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 Pages: 13462-13462
  • Peer Reviewed / Open Access
• [Journal Article] G9a-dependent histone methylation can be induced in G1 phase of cell cycle. (2019)
  • Author(s): Fukuda M, Sakaue-Sawano A, Shimura C, Tachibana M, Miyawaki A, Shinkai Y.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 956-956
  • DOI: 10.1038/s41598-018-37507-5
  • Peer Reviewed / Open Access
• [Journal Article] 性とは何か：雌雄間の多様な性 (2019)
  • Author(s): 立花誠
  • Journal Title: 現代化学 Volume: 574 Pages: 40-43
• [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] DNMTs and SETDB1 function as co-repressors in MAX-mediated repression of germ cell-related genes in mouse embryonic stem cells (2018)
  • Author(s): Tatsumi Daiki、Hayashi Yohei、Endo Mai、Kobayashi Hisato、Yoshioka Takumi、Kiso Kohei、Kanno Shinichiro、Nakai Yuji、Maeda Ikuma、Mochizuki Kentaro、Tachibana Makoto、Koseki Haruhiko、Okuda Akihiko、Yasui Akira、Kono Tomohiro、Matsui Yasuhisa
  • Journal Title: PLOS ONE Volume: 13 Issue: 11 Pages: e0205969-e0205969
  • DOI: 10.1371/journal.pone.0205969
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] タンパク質・核酸の修飾ーメチル化 (2018)
  • Author(s): 前田亮、立花誠
  • Journal Title: 生体の化学 Volume: 69 Pages: 404-405
• [Journal Article] タンパク質・核酸の修飾ー脱メチル化 (2018)
  • Author(s): 岡下修己、立花誠
  • Journal Title: 生体の化学 Volume: 69 Pages: 406-407
• [Journal Article] Rescuing the aberrant sex development of H3K9 demethylase Jmjd1a-deficient mice by modulating H3K9 methylation balance (2017)
  • Author(s): Shunsuke Kuroki, Naoki Okashita, Baba Shoko, Maeda Ryo, Shingo Miyawaki, Masashi Yano, Yamaguchi Miyoko, Kitano Satsuki, Miyachi Hitoshi, Itoh Akihiro, Yoshida Minoru and Makoto Tachibana
  • Journal Title: PLoS Genetics Volume: 13(9) Issue: 9 Pages: 1-22
  • DOI: 10.1371/journal.pgen.1007034
  • NAID: 120006812002
  • Peer Reviewed / Open Access
• [Journal Article] Impact of histone demethylase KDM3A-dependent AP-1 transactivity on hepatotumorigenesis induced by PI3K activation. (2017)
  • Author(s): Nakatsuka T, Tateishi K, Kudo Y, Yamamoto K, Nakagawa H, Fujiwara H, Takahashi R, Miyabayashi K, Asaoka Y, Tanaka Y, Ijichi H, Hirata Y, Otsuka M, Kato M, Sakai J, Tachibana M, Aburatani H, Shinkai Y, *Koike K.
  • Journal Title: Oncogene Volume: 印刷中 Issue: 45 Pages: 6262-6271
  • DOI: 10.1038/onc.2017.222
  • Peer Reviewed
• [Journal Article] Essential roles of G9a in cell proliferation and differentiation during tooth development. (2017)
  • Author(s): Taichi Kamiunten, Hisashi Ideno, Akemi Shimada, Yoshinori Arai, Tatsuo Terashima, Yasuhiro Tomooka, Yoshii Nakamura, Kazuhisa Nakashima, Hiroshi Kimura, Yoichi Shinkai, Makoto Takchibana, Akira Nifuji
  • Journal Title: Experimental ell Research Volume: 357 Issue: 2 Pages: 202-210
  • DOI: 10.1016/j.yexcr.2017.05.016
  • 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] マウスES細胞におけるトランスポゾンの抑制機構 (2021)
  • Author(s): 立花 誠
  • Organizer: 転移因子研究会
  • Invited
• [Presentation] Epigenetic regulation of two-cell-specific genes in mouse ES cells (2021)
  • Author(s): 立花 誠
  • Organizer: 日本分子生物学会
  • Invited
• [Presentation] HP1-dependent heterochromatin formation in mammalian cells (2021)
  • Author(s): Ryo Maeda, Makoto Tachibana
  • Organizer: 染色体ワークショップ
• [Presentation] 真のオス化因子をコードするマウスSryの”隠れ”エキソンの発見 (2021)
  • Author(s): 立花 誠
  • Organizer: 日本エピジェネティクス研究会
  • Invited
• [Presentation] マウスSry遺伝子座には、これまで未同定でかつオス化に必須な役割を有する第2エキソンが存在する (2020)
  • Author(s): 立花 誠
  • Organizer: 日本分子生物学会
  • Invited
• [Presentation] 哺乳類の生殖における抑制的ヒストン修飾の役割 (2019)
  • Author(s): 立花誠
  • Organizer: 2019 遺伝研研究会 有性生殖に関わる染色体・クロマチン・核動態に関する研究会
  • Invited
• [Presentation] マウス性決定におけるエピゲノム制御の役割 (2019)
  • Author(s): 立花誠
  • Organizer: 日本DoHAD学会学術集会シンポジウム
  • Invited
• [Presentation] H3K9のメチル化による生殖機能のエピジェネティック制御 (2019)
  • Author(s): 立花誠
  • Organizer: 日本遺伝学会第91回大会
  • Invited
• [Presentation] Function of HP1 in H3K9 methylation dynamics (2019)
  • Author(s): 立花誠
  • Organizer: 第42回日本分子生物学会年会シンポジウム
  • Invited
• [Presentation] マウスY染色体のInverted repeat配列に存在すr新規性決定領域の発見 (2019)
  • Author(s): 宮脇慎吾、黒木俊介、前田亮、岡下修己、立花誠
  • Organizer: 第42回日本分子生物学会年会ワークショップ
  • Int'l Joint Research / Invited
• [Presentation] Dynamic regulation of H3K9 methylation in germ cell development (2019)
  • Author(s): Makoto Tachibana
  • Organizer: Gordon Research Conferences on Germinal Stem Cell Bilogy, Hong Kong, China
• [Presentation] H3K9 methylation dynamics for mammalian reproduction (2018)
  • Author(s): Makoto Tachibana
  • Organizer: The 8th International symposium on vertebrate sex determination
  • Int'l Joint Research
• [Presentation] ほ乳類の性決定におけるエピゲノム制御の役割 (2018)
  • Author(s): 立花誠
  • Organizer: 第91回日本内分泌学会総会シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] 哺乳類の性決定におけるエピゲノム制御の役割 (2018)
  • Author(s): 立花誠
  • Organizer: 再生学異分野融合研究会
  • Invited
• [Presentation] 哺乳類性決定のエピジェネティックな制御機構 (2018)
  • Author(s): 立花誠
  • Organizer: 第37回動物生殖工学研究会
  • Invited
• [Presentation] H3K9のメチル化修飾によるほ乳類の発生・分化の制御 (2017)
  • Author(s): 立花誠
  • Organizer: 熊本大学発生医学研究所学術セミナー
  • Invited
• [Presentation] Role of H3K9 methylation dynamics for mammalian reproduction (2017)
  • Author(s): Makoto Tachibana
  • Organizer: RIKEN Epigenetics seminar series
  • Invited
• [Presentation] ヒストンのメチル化修飾による生命機能の制御 (2017)
  • Author(s): 立花誠
  • Organizer: 九州大学生体防御医学研究所学術セミナー
  • Invited
• [Presentation] ほ乳類性決定におけるエピゲノム制御の役割 (2017)
  • Author(s): 立花誠
  • Organizer: New Insights of Molecular Genetics on Growth Disorders
  • Invited
• [Presentation] エピジェネティック制御によるほ乳類のオス化の仕組み (2017)
  • Author(s): 立花誠
  • Organizer: 東京大学医科学研究所ゲノム創薬・医療フォーラム
  • Invited
• [Presentation] H3K9のメチル化の動的変動によるほ乳類の発生・分化制御 (2017)
  • Author(s): 立花誠
  • Organizer: 日本分子生物学会2017年度生命科学系学会シンポジウム
  • Invited
• [Book] エピジェネティクス実験スタンダード (2017)
  • Author(s): 立花誠
  • Total Pages: 394
  • Publisher: 羊土社
• [Remarks] 性スペクトラムー連続する表現型としての雌雄ー
  • URL: http://park.itc.u-tokyo.ac.jp/sexspectrum/index.html
• [Remarks] 大阪大学大学院生命機能研究科 立花研究室
  • URL: https://tachibana-lab.net/
• [Remarks] 大阪大学大学院生命機能研究科立花研究室
  • URL: http://www.fbs.osaka-u.ac.jp/jpn/general/lab/072/
• [Remarks] 新学術研究領域「性スペクトラム」
  • URL: http://park.itc.u-tokyo.ac.jp/sexspectrum/
• [Remarks] 徳島大学先端酵素学研究所 エピゲノム動態学分野 HP
  • URL: https://ouyoukouso01.ait231.tokushima-u.ac.jp/
• [Remarks] 新学術領域研究「性スペクトラム」
  • URL: http://park.itc.u-tokyo.ac.jp/sexspectrum/
• [Funded Workshop] Asian Sex Differentiation Network (2017)