Developmental regulation of genome stability in the germline stem cell cycle in mice

• Project/Area Number: 18H02429
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43060:System genome science-related
• Research Institution: Kyoto University
• Principal Investigator: Chuma Shinichiro 京都大学, ウイルス・再生医科学研究所, 准教授 (20378889)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: ゲノム / 遺伝 / 発生 / 生殖 / 幹細胞

Outline of Final Research Achievements

Genetic information is continuously modified by DNA damage and repair. In multicellular organisms, the genetic stability is differentially regulated depending on developmental stages and cell types. Among the various cell lineages, germline cells and stem cell systems are thought to maintain their genetic information more stably than differentiated somatic cells. However, how the genetic stability is properly coordinated with developmental programs is still not well understood. In this study, we carried out in depth comparative analyses of the genetic stability of mouse embryonic stem (ES) cells, their in vitro differentiated derivatives (ectoderm and mesendoderm etc), germline stem (GS) cells and embryonic fibroblasts etc. We obtained the proof of concept (POC) that the genetic stability of mouse embryonic stem cells can be artificially enhanced by modulating cell cycle activities and metabolic pathways while maintaining pluripotent differentiation capacities in vitro.

Academic Significance and Societal Importance of the Research Achievements

本研究課題では、個体発生の起点となる初期発生過程および生殖系列細胞の遺伝的安定性に関わる制御機構を明らかにする目的で、ES細胞、GS細胞、分化体細胞等のDNA損傷応答や染色体安定性に関わる詳細な比較データを得た。また、ES細胞の多能性を維持しつつ染色体安定性を人為的に向上する幾つかの特異的経路の候補を同定した。これらの結果は、発生生物学、遺伝学など基礎生物学的に重要なだけでなく、再生医科学領域等において期待が寄せられている幹細胞リソースの安定供給の為の技術開発の基盤となる事が期待される。

Research Products

• [Journal Article] Genome-Wide Analysis of Differentially Expressed miRNAs and Their Associated Regulatory Networks in Lenses Deficient for the Congenital Cataract-Linked Tudor Domain Containing Protein TDRD7 (2021)
  • Author(s): Anand Deepti、Al Saai Salma、Shrestha Sanjaya K.、Barnum Carrie E.、Chuma Shinichiro、Lachke Salil A.
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 9 Pages: 615761-615761
  • DOI: 10.3389/fcell.2021.615761
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Increased predominance of the matured ventricular subtype in embryonic stem cell-derived cardiomyocytes in vivo (2020)
  • Author(s): Ichimura Hajime、Kadota Shin、Kashihara Toshihide、Yamada Mitsuhiko、Ito Kuniaki、Kobayashi Hideki、Tanaka Yuki、Shiba Naoko、Chuma Shinichiro、Tohyama Shugo、Seto Tatsuichiro、Okada Kenji、Kuwahara Koichiro、Shiba Yuji
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 11883-11883
  • DOI: 10.1038/s41598-020-68373-9
  • NAID: 120007006223
  • Peer Reviewed / Open Access
• [Journal Article] The Tudor-domain protein TDRD7, mutated in congenital cataract, controls the heat shock protein HSPB1 (HSP27) and lens fiber cell morphology (2020)
  • Author(s): Barnum Carrie E、Al Saai Salma、Patel Shaili D、Cheng Catherine、Anand Deepti、Xu Xiaolu、Dash Soma、Siddam Archana D、Glazewski Lisa、Paglione Emily、Polson Shawn W、Chuma Shinichiro、Mason Robert W、Wei Shuo、Batish Mona、Fowler Velia M、Lachke Salil A
  • Journal Title: Human Molecular Genetics Volume: 29 Issue: 12 Pages: 2076-2097
  • DOI: 10.1093/hmg/ddaa096
  • NAID: 120007006225
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] MEIOSIN directs the switch from mitosis to meiosis in mammalian germ cells (2020)
  • Author(s): Ishiguro K* (Corresponding), Matsuura K, Tani N, Takeda N, Usuki S, Yamane M, Sugimoto M, Fujimura S, Hosokawa M, Chuma S, Ko S.H.M, Araki K, Niwa H
  • Journal Title: Dev. Cell Volume: 52 Issue: 4 Pages: 429-445
  • DOI: 10.1016/j.devcel.2020.01.010
  • Peer Reviewed
• [Journal Article] Overexpression of Nuclear Receptor 5A1 Induces and Maintains an Intermediate State of Conversion between Primed and Naive Pluripotency (2020)
  • Author(s): Yamauchi Kaori、Ikeda Tatsuhiko、Hosokawa Mihoko、Nakatsuji Norio、Kawase Eihachiro、Chuma Shinichiro、Hasegawa Kouichi、Suemori Hirofumi
  • Journal Title: Stem Cell Reports Volume: 14 Issue: 3 Pages: 506-519
  • DOI: 10.1016/j.stemcr.2020.01.012
  • NAID: 120007006224
  • Peer Reviewed / Open Access
• [Journal Article] GPAT2 is required for piRNA biogenesis, transposon silencing, and maintenance of spermatogonia in mice. (2019)
  • Author(s): Shiromoto Y, Kuramochi-Miyagawa S, Nagamori I, Chuma S, Arakawa T, Nishimura T, Hasuwa H, Tachibana T, Ikawa M, Nakano T.
  • Journal Title: Biol Reprod. Volume: Apr 5. Issue: 1 Pages: 248-256
  • DOI: 10.1093/biolre/ioz056
  • Peer Reviewed
• [Journal Article] Mouse GTSF1 is an essential factor for secondary piRNA biogenesis (2018)
  • Author(s): Yoshimura Takuji、Watanabe Toshiaki、Kuramochi‐Miyagawa Satomi、Takemoto Noriaki、Shiromoto Yusuke、Kudo Akihiko、Kanai‐Azuma Masami、Tashiro Fumi、Miyazaki Satsuki、Katanaya Ami、Chuma Shinichiro、Miyazaki Jun‐ichi
  • Journal Title: EMBO Reports Volume: 19 Issue: 4
  • DOI: 10.15252/embr.201642054
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Meiosis priming program and genome stability control of the germline stem cell cycle in mouse development (2020)
  • Author(s): Shinchiro Chuma
  • Organizer: MBSJ2000
• [Presentation] 生殖系列サイクルの発生段階に応じた遺伝的安定性の調節機構 (2019)
  • Author(s): 中馬新一郎
  • Organizer: 遺伝研研究会「有性生殖にかかわる染色体・クロマチン・核動態に関する研究会」
  • Invited
• [Presentation] PARI regulates both replication stress response and DNA damage response to maintain genome stability in mice. (2019)
  • Author(s): Ayako L. Mochizuki, Ami Katanaya, Eri Hayashi, Mihoko Hosokawa, Emiko Moribe, Akira Motegi, Masamichi Ishiai, Minoru Takata, Gen Kondoh, Hitomi Watanabe, Norio Nakatsuji, Shinichiro Chuma.
  • Organizer: ICRR2019
• [Presentation] PARI Regulates Stalled Replication Fork Processing To Maintain Genome Stability upon Replication Stress in Mice (2018)
  • Author(s): 中馬新一郎
  • Organizer: 新学術領域研究「生殖細胞のエピゲノムダイナミクスとその制御」成果取りまとめ公開シンポジウム
  • Int'l Joint Research