Omics approaches towards the elucidation of the molecular network regulating the developmental capacity of the mammalian oocyte

• Project/Area Number: 18H05214
• Research Category: Grant-in-Aid for Specially Promoted Research
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyushu University
• Principal Investigator: SASAKI Hiroyuki 九州大学, 生体防御医学研究所, 特別主幹教授 (30183825)
• Co-Investigator(Kenkyū-buntansha): 丸山 修 九州大学, 芸術工学研究院, 准教授 (20282519)
• Project Period (FY): 2018-04-23 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥508,560,000 (Direct Cost: ¥391,200,000、Indirect Cost: ¥117,360,000); Fiscal Year 2022: ¥61,490,000 (Direct Cost: ¥47,300,000、Indirect Cost: ¥14,190,000); Fiscal Year 2021: ¥94,640,000 (Direct Cost: ¥72,800,000、Indirect Cost: ¥21,840,000); Fiscal Year 2020: ¥88,790,000 (Direct Cost: ¥68,300,000、Indirect Cost: ¥20,490,000); Fiscal Year 2019: ¥145,340,000 (Direct Cost: ¥111,800,000、Indirect Cost: ¥33,540,000); Fiscal Year 2018: ¥118,300,000 (Direct Cost: ¥91,000,000、Indirect Cost: ¥27,300,000)
• Keywords: 卵子 / オミックス / ゲノム編集 / 機械学習 / 発生 / エピジェネティクス

Outline of Final Research Achievements

By applying genome editing and small-scale omics approaches, we have revealed the molecular network regulating histone modifications and DNA methylation in mouse oocytes, which are essential for mammalian development. We discovered that several histone modifications impact the efficiency and distribution of DNA methylation and identified the proteins and their domains that mediate the epigenetic crosstalk. Further, we found that, while DNA methylation established in oocytes regulates the expression of the maternally imprinted genes almost exclusively in embryos, histone modifications and their responsive factors have a wider effect and regulate various cellular function including chromosome segregation. Finally, we developed a machine-learning-based model that predicts the heritability of DNA methylation to the next generation based on DNA sequence. The findings provide a basis for the study of infertility, various diseases, and improvement of assisted reproductive technologies.

Academic Significance and Societal Importance of the Research Achievements

我々が明らかにしたマウス卵子におけるヒストン修飾とDNAメチル化の分子ネットワークは、不妊・流産・先天異常の原因解明、及び生殖補助医療技術の改善に資すると考えられ、ヒト人工多能性幹細胞から誘導された卵細胞のエピゲノムデータは、この細胞の学術的・臨床的応用に向けて貴重な情報リソースである。また、我々が開発した数理モデルは、子宮内環境や種々の環境ストレスにより生じたエピゲノム異常の次世代への伝達の予測に役立つほか、その機構の解明に貢献すると期待される。

Assessment Rating

Ex-post Assessment Comments (Rating)

A: In light of the aim of introducing the research area into the research categories, expected outcomes of research have been produced.

Research Products

• [Int'l Joint Research] University of California Davis/UT Health San Antonio(米国)
• [Int'l Joint Research] University of British Columbia(カナダ)
• [Int'l Joint Research] University of British Columbia(カナダ)
• [Int'l Joint Research] 清華大学/北京大学/中国科学院(中国)
• [Int'l Joint Research] Friedrich Miescher Institute/University of Basel(スイス)
• [Int'l Joint Research] Vienna Biocenter(オーストリア)
• [Int'l Joint Research] Max Planck Institute of Biochemistry(ドイツ)
• [Int'l Joint Research] Institute of Molecular Genetics/CNRS/University of Montpellier(フランス)
• [Int'l Joint Research] University of British Columbia(カナダ)
• [Journal Article] The UHRF protein family in epigenetics, development, and carcinogenesis (2022)
  • Author(s): UNOKI Motoko、SASAKI Hiroyuki
  • Journal Title: Proceedings of the Japan Academy, Series B Volume: 98 Issue: 8 Pages: 401-415
  • DOI: 10.2183/pjab.98.021
  • ISSN: 0386-2208, 1349-2896
  • Year and Date: 2022-10-11
  • Peer Reviewed / Open Access
• [Journal Article] Histone H3K36me2 and H3K36me3 form a chromatin platform essential for DNMT3A-dependent DNA methylation in mouse oocytes (2022)
  • Author(s): Yano Seiichi、Ishiuchi Takashi、Abe Shusaku、Namekawa Satoshi H.、Huang Gang、Ogawa Yoshihiro、Sasaki Hiroyuki
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 4440-4440
  • DOI: 10.1038/s41467-022-32141-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CMIC: predicting DNA methylation inheritance of CpG islands with embedding vectors of variable-length k-mers (2022)
  • Author(s): Maruyama Osamu、Li Yinuo、Narita Hiroki、Toh Hidehiro、Au Yeung Wan Kin、Sasaki Hiroyuki
  • Journal Title: BMC Bioinformatics Volume: 23 Issue: 1 Pages: 371-371
  • DOI: 10.1186/s12859-022-04916-3
  • Peer Reviewed / Open Access
• [Journal Article] Low Input Genome-Wide DNA Methylation Analysis with Minimal Library Amplification (2022)
  • Author(s): Au Yeung Wan Kin、Sasaki Hiroyuki
  • Journal Title: Methods in Molecular Biology Volume: 2509 Pages: 233-250
  • DOI: 10.1007/978-1-0716-2380-0_14
  • ISBN: 9781071623794, 9781071623800
  • Peer Reviewed
• [Journal Article] The DNMT3A PWWP domain is essential for the normal DNA methylation landscape in mouse somatic cells and oocytes (2021)
  • Author(s): Kibe Kanako、Shirane Kenjiro、Ohishi Hiroaki、Uemura Shuhei、Toh Hidehiro、Sasaki Hiroyuki
  • Journal Title: PLOS Genetics Volume: 17 Issue: 5 Pages: e1009570-e1009570
  • DOI: 10.1371/journal.pgen.1009570
  • Peer Reviewed / Open Access
• [Journal Article] A convolutional neural network-based regression model to infer the epigenetic crosstalk responsible for CG methylation patterns (2021)
  • Author(s): Au Yeung Wan Kin、Maruyama Osamu、Sasaki Hiroyuki
  • Journal Title: BMC Bioinformatics Volume: 22 Issue: 1 Pages: 341-341
  • DOI: 10.1186/s12859-021-04272-8
  • Peer Reviewed / Open Access
• [Journal Article] Production of functional oocytes requires maternally expressed PIWI genes and piRNAs in golden hamsters (2021)
  • Author(s): Hasuwa Hidetoshi、Iwasaki Yuka W.、Au Yeung Wan Kin、Ishino Kyoko、Masuda Harumi、Sasaki Hiroyuki、Siomi Haruhiko
  • Journal Title: Nature Cell Biology Volume: 23 Issue: 9 Pages: 1002-1012
  • DOI: 10.1038/s41556-021-00745-3
  • Peer Reviewed / Open Access
• [Journal Article] Reprogramming of the histone H3.3 landscape in the early mouse embryo. (2021)
  • Author(s): Ishiuchi, T., Abe, S., Inoue, K., Au Yeung, W.K., Miki, Y., Ogura, A. & Sasaki, H.
  • Journal Title: Nature Structural & Molecular Biology Volume: 28 Issue: 1 Pages: 38-49
  • DOI: 10.1038/s41594-020-00521-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Maternal DNMT3A-dependent de novo methylation of the paternal genome inhibits gene expression in the early embryo. (2020)
  • Author(s): Richard Albert, J., Au Yeung, W.K., Toriyama, K., Kobayashi, H., Hirasawa, R., Brind’Amour, J., Bogutz, A., Sasaki, H. & Lorincz, M.
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 5417-5417
  • DOI: 10.1038/s41467-020-19279-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Polycomb group proteins regulate chromatin architecture in mouse oocytes and early embryos. (2020)
  • Author(s): Du, Z., Zheng, H., Kawamura, Y.K., Zhang, K., Gassler, J., Powell, S., Xu, Q., Lin, Z., Xu, K., Zhou, Q., Ozonov, E.A., Veron, N., Huang, B., Li, L., Yu, G., Liu, L., Au Yeung, W.K., Wang, P., Chang, L., Wang, Q., He, A., Sun, Y., Na, J., Sun, Q., Sasaki, H., Tachibana, K., Peters, A.H.F.M. & Xie, W.
  • Journal Title: Molecular Cell Volume: 77 Issue: 4 Pages: 825-839
  • DOI: 10.1016/j.molcel.2019.11.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Characterization of genetic‐origin‐dependent monoallelic expression in mouse embryonic stem cells (2019)
  • Author(s): Ohishi Hiroaki、Au Yeung Wan Kin、Unoki Motoko、Ichiyanagi Kenji、Fukuda Kei、Maenohara Shoji、Shirane Kenjiro、Chiba Hatsune、Sado Takashi、Sasaki Hiroyuki
  • Journal Title: Genes to Cells Volume: 25 Issue: 1 Pages: 54-64
  • DOI: 10.1111/gtc.12736
  • Peer Reviewed / Open Access
• [Journal Article] Low-input ChlP-seqの現状. (2019)
  • Author(s): 1.石内崇士, 榊原祐樹, 佐々木裕之.
  • Journal Title: 臨床免疫・アレルギー科 Volume: 72 Pages: 283-286
• [Journal Article] Genomic imprinting and physiological processes in mammals (2019)
  • Author(s): Tucci, V., Isles, A.R., Kelsey, G., Ferguson-Smith, A.C., Bartolomei, M.S, Benvenisty, N., Bourc’his, D., Charalambous, M., Dulac, C., Feil, R., Glaser, J., Huelsmann, L., John, R.M., McNamara, G.I., Moorwood, K., Muscatelli, F., Sasaki, H., Strassmann, B.I., Vincenz, C., Wilkins, J.
  • Journal Title: Cell Volume: 176 Issue: 5 Pages: 952-965
  • DOI: 10.1016/j.cell.2019.01.043
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Generation of human oogonia from induced pluripotent stem cells in vitro. (2018)
  • Author(s): 30.Yamashiro C, Sasaki K, Yabuta Y, Kojima Y, Nakamura T, Okamoto I, Yokobayashi S, Murase Y, Ishikura Y, Shirane K, Sasaki H, Yamamoto T, Saitou M.
  • Journal Title: Science Volume: 362(6412) Issue: 6412 Pages: 356-360
  • DOI: 10.1126/science.aat1674
  • Peer Reviewed
• [Journal Article] エピジェネティクスと蛋白質生合成の制御. (2018)
  • Author(s): 阿部周策，佐々木裕之
  • Journal Title: 医学のあゆみ Volume: 267 Pages: 893-897
• [Presentation] 早期ライフステージにおける環境ストレスとエピジェネティクス (2023)
  • Author(s): 佐々木裕之
  • Organizer: 第30回日本ステロイドホルモン学会学術集会
  • Invited
• [Presentation] Regulation of DNA methylation and imprinting in mouse oocytes (2023)
  • Author(s): Hiroyuki Sasaki
  • Organizer: The 36th International mammalian Genome Conference (IMGC2023)
  • Int'l Joint Research / Invited
• [Presentation] マウス卵子の発生能とエピゲノム修飾の相互作用ネットワーク (2022)
  • Author(s): 佐々木裕之
  • Organizer: 第15回日本エピジェネティクス研究会年会
  • Invited
• [Presentation] 卵子のエピジェネティクスと発生能 (2022)
  • Author(s): 佐々木裕之
  • Organizer: ART FORUM’22
  • Invited
• [Presentation] 運命と偶然のはざまを科学する: 私のエピジェネティクス研究 (2022)
  • Author(s): 佐々木裕之
  • Organizer: 日本遺伝学会第94回大会
  • Invited
• [Presentation] Multiple histone-interaction regulates DNMT3A mediating DNA methylation and imprinting in mouse oocytes (2022)
  • Author(s): Hiroyuki Sasaki
  • Organizer: The International Symposium “Totipotency and Germ Cell Development”
  • Int'l Joint Research / Invited
• [Presentation] Recurrent neural network approach for predicting DNA methylation inheritance of CpG islands using embedding vectors of variable length k-mers (2022)
  • Author(s): Osamu Maruyama
  • Organizer: The International Symposium “Totipotency and Germ Cell Development”
  • Int'l Joint Research / Invited
• [Presentation] Establishment of the proper DNA methylation landscape requires the DNMT3A domains recognizing histone modifications in mouse oocytes (2022)
  • Author(s): Hiroyuki Sasaki
  • Organizer: The 30th Hot Spring Harbor International Symposium, Chromatin Potential in Development & Differentiation, The 6th Symposium of the Inter-University Research Network for Trans-Omics Medicine
  • Int'l Joint Research / Invited
• [Presentation] 哺乳類の生殖細胞におけるエピジェネティクス制御の仕組みを探る (2022)
  • Author(s): 佐々木裕之
  • Organizer: 先端モデル動物支援プラットフォーム成果発表会
  • Invited
• [Presentation] 埋め込みベクトルによるCpGアイランドのメチル化状態予測 (2022)
  • Author(s): 成田浩規, Au Yeung Wan Kin, 佐々木裕之, 丸山修
  • Organizer: 情報処理学会第69回BIO研究発表会
• [Presentation] 予測と偶然の科学：エピジェネティクス (2022)
  • Author(s): 佐々木裕之
  • Organizer: 大阪大学蛋白質研究所セミナー: 生殖細胞-減数分裂シンポジウム
  • Invited
• [Presentation] エピゲノム研究の現状と医学生物学への応用 (2021)
  • Author(s): 佐々木裕之
  • Organizer: 第15回ケミカルバイオロジー学会
  • Invited
• [Presentation] ヒトエピゲノム研究の現状と医学応用 (2021)
  • Author(s): 佐々木裕之
  • Organizer: 第71回日本体質医学会総会
  • Invited
• [Presentation] A machine learning model to infer the epigenetic crosstalk responsible for CG methylation patterns (2021)
  • Author(s): Wan Kin Au Yeung, Osamu Maruyama & Hiroyuki Sasaki
  • Organizer: 日本遺伝学会第93回大会
• [Presentation] Molecular network regulating the epigenetic program of mammalian oocytes (2021)
  • Author(s): 佐々木裕之
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] Histone H3K36me2 and H3K36me3 form a chromatin platform essential for DNMT3A-dependent DNA methylation in mouse oocytes (2021)
  • Author(s): Seiichi Yano, Takashi Ishiuchi, Shusaku Abe, Satoshi Namekawa, Gang Huang & Hiroyuki Sasaki
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] DNA methylation in development and disease. (2021)
  • Author(s): Hiroyuki Sasaki
  • Organizer: Genome Concept Centennial Symposium
  • Int'l Joint Research / Invited
• [Presentation] Predicting Discriminative Motifs for DNA Methylation in Mammalian Development. (2020)
  • Author(s): Ryo Shimizu, Wan Kin Au Yeung, Hidehiro Toh, Hiroyuki Sasaki, Osamu Maruyama
  • Organizer: 2020年日本バイオインフォマティクス学会年会・第９回生命医薬情報学連合大会
• [Presentation] ヒトエピゲノム研究の現状と医学応用. (2020)
  • Author(s): 佐々木裕之
  • Organizer: 第31回日本緑内障学会
  • Invited
• [Presentation] Genomic imprinting as a model to study epigenetic inheritance and reprogramming. (2020)
  • Author(s): Hiroyuki Sasaki
  • Organizer: 第43回日本分子生物学会年会
  • Invited
• [Presentation] Molecular network regulating the epigenetic programs of mammalian oocytes. (2019)
  • Author(s): Sasaki, H.
  • Organizer: 第13回日本エピジェネティクス研究会年会
  • Invited
• [Presentation] マウス卵子のエピゲノム制御ネットワーク. (2019)
  • Author(s): 佐々木裕之.
  • Organizer: 2019遺伝研研究会
  • Invited
• [Presentation] DNAメチル化と疾患. (2019)
  • Author(s): 佐々木裕之.
  • Organizer: 第78回日本癌学会学術総会
  • Invited
• [Presentation] Epigenetic program of mammalian oocytes. (2019)
  • Author(s): Hiroyuki Sasaki
  • Organizer: 理化学研究所エピゲノム操作プロジェクトセミナー
  • Invited
• [Presentation] エピジェネティクスと細胞記憶と疾患. (2019)
  • Author(s): 佐々木裕之
  • Organizer: 大阪大学微生物病研究所セミナー学術講演会
  • Invited
• [Presentation] Role of UHRF1 in de novo DNA methylation in oocytes and maintenance methylation in preimplantation embryos. (2018)
  • Author(s): Sasaki, H.
  • Organizer: Cold Spring Harbor Asia Conference: Chromatine, Epigenetics & Transcription 2018 (Suzhou)
  • Int'l Joint Research / Invited
• [Presentation] エピジェネティクスと細胞記憶と疾患 (2018)
  • Author(s): 佐々木裕之
  • Organizer: 平成30年度日本生化学会九州支部例会（福岡）
  • Invited
• [Presentation] エピジェネティクスと細胞記憶と疾患 (2018)
  • Author(s): 佐々木裕之
  • Organizer: 第60回歯科基礎医学会学術大会（福岡）
  • Invited
• [Presentation] Distinct roles of epigenetic regulators in mouse oocytes and somatic sells. (2018)
  • Author(s): Sasaki, H.
  • Organizer: Cold Spring Harbor Meeting: Epigenetics & Chromatin (New York)
  • Int'l Joint Research / Invited
• [Presentation] Histone H3K9 methyltransferase G9a in oocyte is essential for preimplantation development but dispensable for CG methylation protection. (2018)
  • Author(s): Au Yeung, W.K., Brind'Amour, J., Hatano, Y., Yamagata, K., Feil, R., Lorincz, M.C., Tachibana, M., Shinkai, Y., Sasaki, H.
  • Organizer: International Human Epigenome Consortium Annual Meeting 2018 (Hong Kong)
  • Int'l Joint Research
• [Book] もっとよくわかる！エピジェネティクス. 実験医学別冊 (2020)
  • Author(s): 鵜木元香, 佐々木裕之
  • Total Pages: 188
  • Publisher: 羊土社
  • ISBN: 9784758122078
• [Remarks] 九州大学生体防御医学研究所エピゲノム制御学分野
  • URL: https://www.bioreg.kyushu-u.ac.jp/labo/epigenome/
• [Remarks] 九州大学芸術工学研究院丸山研究室
  • URL: http://www.design.kyushu-u.ac.jp/-maruyama/
• [Remarks] 九州大学芸術工学研究院丸山研究室
  • URL: http://www.design.kyushu-u.ac.jp/~maruyama/
• [Remarks] 九州大学芸術工学院丸山研究室
  • URL: http://www.design.kyushu-u.ac.jp/~maruyama/
• [Remarks] 九州大学生体防御医学研究所エピゲノム制御学分野
  • URL: http://www.bioreg.kyushu-u.ac.jp/labo/epigenome/
• [Funded Workshop] The International Symposium “Totipotency and Germ Cell Development” (2022)
• [Funded Workshop] The International Symposium "Totipotency and Germ Cell Development" (2022)