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Metabolic and epigenetic regulation of pluripotency via FLCN-RAG-TFE axis

Research Project

Project/Area Number 19K06693
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 44020:Developmental biology-related
Research InstitutionKumamoto University

Principal Investigator

Endoh Mitsuhiro  熊本大学, 発生医学研究所, 助教 (40391883)

Co-Investigator(Kenkyū-buntansha) 須田 年生  熊本大学, 国際先端医学研究機構, 卓越教授 (60118453)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords多能性幹細胞 / 胚性幹細胞 / ES細胞 / 多能性 / リソソーム / 転写因子 / 初期発生 / 幹細胞 / ライソソーム / アミノ酸代謝 / ナイーブ型 / 代謝 / 着床 / 発生 / シグナル伝達 / エピジェネティクス
Outline of Research at the Start

胚の着床前後では栄養代謝の相違が予想されるが、多能性への影響とメカニズムは不明である。着床前胚から作製される胚性幹細胞(ES細胞)と、着床後胚から作製されるエピブラスト幹細胞は、それぞれナイーブ型、プライム型と呼ばれる異なる形質を持つ多能性幹細胞である。本研究では、アミノ酸センシング機構として働くFLCN-RagGTPase-TFE3/B経路による栄養代謝の役割に注目し、ナイーブ型とプライム型の多能性の決定・維持への関与を明らかにする。またこの代謝経路と、転写因子ネットワークおよびエピジェネティクスとのクロストークの解析を行い、多能性幹細胞を規定する種を超えた普遍的な分子機構の理解を目指す。

Outline of Final Research Achievements

Deletion of Flcn in ES cells resulted in permanent nuclear localization of Tfe3 and LIF-independent self-renewal, whereas further deletion of Tfe3 resulted in loss of this phenotype. Forced activation of Tfe3 also resulted in the LIF-independent self-renewal phenotype, and this phenotype was dependent on the naive pluripotency factors Esrrb and Nanog. Since ES cells deficient in both Tfe3 and Tfeb could not be established and maintained, Tfe3/Tfeb may contribute to ES cell maintenance in a coordinated manner. Mouse blastocysts with constitutively activated TFE3 could be maintained for a certain period of time in vitro, suggesting that TFE3 may contribute to the maintenance of preimplantation embryos.

Academic Significance and Societal Importance of the Research Achievements

マウスES細胞および初期胚を用いた研究を通して、リソソーム生合成のマスター転写因子であるTFE3を活性化させることにより、着床前胚の多能性状態を維持することが可能であることが分かった。この研究成果は、リソソームを介したエネルギー代謝活性の変化が多能性の遷移に関与する可能性を明らかにした点において、学術的に重要な知見である。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (14 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (3 results) Journal Article (4 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (6 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results) Book (1 results)

  • [Int'l Joint Research] シンガポール国立大学がん科学研究所(シンガポール)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] シンガポール国立大学がん科学研究所(シンガポール)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] National University of Singapore(シンガポール)

    • Related Report
      2019 Research-status Report
  • [Journal Article] Mitochondria transfer from early stages of erythroblasts to their macrophage niche via tunnelling nanotubes2021

    • Author(s)
      Yang C, Endoh M, Tan DQ, Nakamura-Ishizu A, Takihara Y, Matsumura T, Suda T.
    • Journal Title

      Br J Haematol .

      Volume: 193 Issue: 6 Pages: 1260-1274

    • DOI

      10.1111/bjh.17531

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Mitochondria transfer from erythroblasts to their macrophage niche via tunneling nanotubes.2021

    • Author(s)
      Yang C, Endoh M, Tan DQ, Nakamura-Ishizu A, Takihara Y, Matsumura T, Suda T.
    • Journal Title

      British Journal of Haematology

      Volume: In press

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A FLCN-TFE3 Feedback Loop Prevents Excessive Glycogenesis and Phagocyte Activation by Regulating Lysosome Activity2020

    • Author(s)
      Mitsuhiro Endoh, Masaya Baba, Tamie Endoh, Akiyoshi Hirayama, Ayako Nakamura-Ishizu, Terumasa Umemoto, Michihiro Hashimoto, Kunio Nagashima, Tomoyoshi Soga, Martin Lang , Laura S Schmidt , W Marston Linehan, Toshio Suda
    • Journal Title

      Cell Reports

      Volume: 30 Issue: 6 Pages: 1823-1834

    • DOI

      10.1016/j.celrep.2020.01.042

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] High Mitochondrial Mass Is Associated With Reconstitution Capacity and Quiescence of Hematopoietic Stem Cells2019

    • Author(s)
      Yuji Takihara, Ayako Nakamura-Ishizu, Darren Qiancheng Tan, Masahiro Fukuda, Takayoshi Matsumura, Mitsuhiro Endoh, Yuichiro Arima, Desmond Wai Loon Chin, Terumasa Umemoto, Michihiro Hashimoto, Hidenobu Mizuno, Toshio Suda
    • Journal Title

      Blood Advances

      Volume: 3 Issue: 15 Pages: 2323-2327

    • DOI

      10.1182/bloodadvances.2019032169

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Dppa2/4によるナイーブ型多能性に特異的なbivalentクロマチンの制御2022

    • Author(s)
      遠藤充浩、岡野正樹、丹羽仁史
    • Organizer
      第74回日本細胞生物学会大会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Role of PRC1.6 Polycomb complex for repression of ZGA- and germline-related genes in pluripotent stem cells2021

    • Author(s)
      Mitsuhiro Endoh , Haruhiko Koseki , Hitoshi Niwa
    • Organizer
      第18回幹細胞シンポジウム
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Regulation of germline genes by PRC1.6 Polycomb and Dppa2/4 in mouse pluripotent stem cells.2021

    • Author(s)
      遠藤充浩, 遠藤多美枝, 岡野正樹, 丹羽仁史
    • Organizer
      新学術「全能性&非ゲノム複製」領域合同若手研究会2021
    • Related Report
      2020 Research-status Report
  • [Presentation] 転写因子Dppa2/4によるES細胞におけるテロメア長の制御2020

    • Author(s)
      遠藤充浩, 遠藤多美枝, 岡野正樹, 丹羽仁史
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 腎がん抑制遺伝子Folliculinの欠損はリソソーム制御転写因子TFE3の活性化を介してグリコーゲン合成を促進する2019

    • Author(s)
      遠藤充浩、馬場理也、遠藤多美枝、梅本晃正、橋本倫拓、平山明由、須田年生
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] Role of PCGF6-PRC1 Polycomb in regulation of germ cell-related genes in mouse ES cells2019

    • Author(s)
      Mitsuhiro Endoh
    • Organizer
      The 4th Symposium of the Inter-University Research Network for Trans-Omics Medicine
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Book] 生体の科学「多能性の遷移とエピジェネティクス」2021

    • Author(s)
      遠藤充浩、丹羽仁史
    • Total Pages
      6
    • Publisher
      医学書院
    • Related Report
      2021 Annual Research Report 2020 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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