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Elucidation of molecular mechanism of epigenetic memory of FGF21 gene and its functional significance in vivo.

Research Project

Project/Area Number 19K09018
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54040:Metabolism and endocrinology-related
Research InstitutionDokkyo Medical University

Principal Investigator

Hashimoto Koshi  獨協医科大学, 医学部, 教授 (30396642)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
KeywordsCRISPR-dCas9-TET1CD系 / 遺伝子特異的DNA脱メチル化 / FGF21 / PPARα / エピジェネティクス / エピゲノム制御 / エピゲノム記憶 / エピゲノム編集 / DNA脱メチル化 / CRISPR-dCas9 / TET1 / PPARαノックアウトマウス / HTVi / TET / Hepa1-6 / DOHaD学説
Outline of Research at the Start

本研究ではFibroblast growth factor (FGF)21遺伝子特異的なDNA脱メチル化を細胞およびマウス生体に導入することで、FGF21遺伝子のDNAメチル化を介した「エピゲノム記憶」の分子機構を明らかにし、FGF21遺伝子特異的なDNAメチル化状態の変化が生体の代謝表現型に及ぼす影響を解析する。

Outline of Final Research Achievements

Recently, we reported PPARα-dependent DNA demethylation of the Fgf21 promoter in the postnatal mouse liver, where reduced DNA methylation is associated with enhanced gene expression after PPARα activation. However, there is no direct evidence for the effect of site-specific DNA methylation on gene expression. We employed the dCas9-SunTag and single-chain variable fragment (scFv)-TET1 catalytic domain (TET1CD) system to induce targeted DNA methylation of the Fgf21 promoter both in vitro and in vivo. We succeeded in targeted DNA demethylation of the Fgf 21 promoter both in Hepa1-6 cells and PPARα-deficient mice, with increased gene expression response to PPARα synthetic ligand administration and fasting, respectively. This study provides direct evidence that the DNA methylation status of a particular gene may determine the magnitude of the gene expression response to activation cues.

Academic Significance and Societal Importance of the Research Achievements

遺伝子特異的にDNA脱メチル化を導入するエピゲノム改変の研究は世界的にもまだ少なく、本研究は先駆的である。CRISPR-dCAS9-TET1CD系を用いてFGF21遺伝子特異的なDNA脱メチル化を細胞とマウス肝臓に導入した。本研究によりFGF21遺伝子のDNA脱メチル化によるエピゲノム制御の機能的意義が初めて明らかになった。またCRISPR-dCAS9-TET1CD系とPPARαノックアウトマウスを用いた「遺伝子特異的エピゲノム改変動物」は代謝分野において世界で初めての試みである。今後このエピゲノム改変動物を解析することにより、代謝におけるエピゲノム記憶の解明につながることが期待される。

Report

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

    (13 results)

All 2022 2021 2020 2019

All Journal Article (8 results) (of which Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (5 results) (of which Int'l Joint Research: 1 results,  Invited: 4 results)

  • [Journal Article] Seasonal variations and the influence of COVID-19 pandemic on hemoglobin A1c, glycoalbumin, and low-density lipoprotein cholesterol2022

    • Author(s)
      Takebayashi Kohzo、Yamauchi Mototaka、Hara Kenji、Tsuchiya Takafumi、Hashimoto Koshi
    • Journal Title

      Diabetology International

      Volume: 8 Issue: 4 Pages: 1-7

    • DOI

      10.1007/s13340-022-00574-1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association of circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 with inflammatory markers and urinary albumin excretion in patients with type 2 diabetes2021

    • Author(s)
      Takebayashi Kohzo、Suzuki Tatsuhiko、Yamauchi Mototaka、Hara Kenji、Tsuchiya Takafumi、Inukai Toshihiko、Hashimoto Koshi
    • Journal Title

      SAGE Open Medicine

      Volume: 9 Pages: 1-7

    • DOI

      10.1177/20503121211064468

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Serum thyroid-stimulating hormone receptor antibody levels and thyroid dysfunction after hysterosalpingography: a case-control study2021

    • Author(s)
      So Shuhei、Hashimoto Koshi、Mori Masatomo、Endo Shigeki、Yamaguchi Wakasa、Miyano Naomi、Murabayashi Nao、Tawara Fumiko
    • Journal Title

      Gynecological Endocrinology

      Volume: 37 Issue: 10 Pages: 898-901

    • DOI

      10.1080/09513590.2021.1963430

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] DOHaD学説における肥満症の個人差と精密医療への展望2021

    • Author(s)
      橋本 貢士
    • Journal Title

      実験医学

      Volume: 39 Pages: 767-774

    • Related Report
      2021 Annual Research Report
  • [Journal Article] 2型糖尿病および肥満におけるDNAメチル化の最新知見2021

    • Author(s)
      橋本 貢士
    • Journal Title

      医学のあゆみ

      Volume: 276 Pages: 453-457

    • Related Report
      2021 Annual Research Report
  • [Journal Article] 周産期栄養とエピジェネティクス2021

    • Author(s)
      橋本 貢士
    • Journal Title

      小児内科

      Volume: 53 Pages: 1818-1824

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing.2020

    • Author(s)
      Hanzawa N, Hashimoto K, Yuan X, Kawahori K, Tsujimoto K, Hamaguchi M, Tanaka T, Nagaoka Y, Nishina H, Morita S, Hatada I, Yamada T, Ogawa Y.
    • Journal Title

      Sci Rep.

      Volume: 10 Issue: 1 Pages: 5181-5181

    • DOI

      10.1038/s41598-020-62035-6

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ascorbic acid during the suckling period is required for proper DNA demethylation in the liver2020

    • Author(s)
      Kawahori Kenichi、Kondo Yoshitaka、Yuan Xunmei、Kawasaki Yuki、Hanzawa Nozomi、Tsujimoto Kazutaka、Wada Fumiko、Kohda Takashi、Ishigami Akihito、Yamada Tetsuya、Ogawa Yoshihiro、Hashimoto Koshi
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 21228-21228

    • DOI

      10.1038/s41598-020-77962-7

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Developmental Origins of Health and Disease (DOHaD)学説の見地に立った 肝臓でのDNA脱メチル化におけるビタミンCの重要性2021

    • Author(s)
      橋本貢士
    • Organizer
      日本ビタミン学会第73回大会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] エピゲノム改変動物を用いたFibroblast growth factor 21(FGF21)遺伝子DNAメチル化の機能的意義解明2021

    • Author(s)
      辻本 和峰, 橋本 貢士, 榛澤 望, 川堀 健一, 袁 勲梅, 長岡 勇也, 仁科 博史, 畑田 出穂, 山田 哲也, 小川 佳宏
    • Organizer
      第64回日本糖尿病学会年次学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] DOHaD 学説とエピゲノム記憶2020

    • Author(s)
      橋本貢士
    • Organizer
      第42回日本臨床栄養学会総会・第41回日本臨床栄養協会総会 第18回大連合大会 シンポジウム 「栄養シグナルと食物アレルギー」
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Epigenetics in early life, which affects obesity in later life2020

    • Author(s)
      Koshi Hashimoto
    • Organizer
      The International Association of the Diabetes and Pregnancy Study Groups 2020 meeting
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] CRISPR/dCas9 系による Fibroblast growth factor 21 遺伝子特異的 DNA 脱メチル化の導入2019

    • Author(s)
      橋本貢士
    • Organizer
      日本ゲノム編集学会 第4回大会
    • Related Report
      2019 Research-status Report
    • Invited

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

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