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Molecular mechanism and functional meaning of PPARalpha-dependent DNA demethylation of FGF21 gene

Research Project

Project/Area Number 17K01840
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Applied health science
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Yuan Xunmei  東京医科歯科大学, 大学院医歯学総合研究科, 特任助教 (70392404)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
KeywordsPPARα / FGF21 / DNAメチル化 / エピジェネティクス / DOHaD / PGC1α / FGF21遺伝子特異的DNA脱メチル化 / FGF2
Outline of Final Research Achievements

We showed that the fibroblast growth factor 21 gene (FGF21 gene), a metabolic hormone implicated in the regulation of energy homeostasis, is subject to peroxisome proliferator-activated receptor (PPAR) α-dependent DNA demethylation in the liver during the postnatal period. The DNA demethylation status of FGF21 gene is relatively stable and remains into adulthood, which may account in part for the improvement of diet-induced obesity. Metabolic phenotypes were alleviated in FGF21-KO indicating that FGF21 may play a major role in the developmental programming of obesity. We also showed successful targeted site-specific DNA demethylation of FGF21 gene both in Hepa1-6 cells and PPARα-deficient mice, using the dCas9-SunTag and single-chain variable fragment (scFv)-TET1 catalytic domain (TET1CD) system. This study implies great potential of epigenome editing for novel therapies. Molecular mechanism underlying PPARα-dependent DNA demethylation was also discussed.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、乳仔期に確立した代謝関連遺伝子のDNAメチル化状態が長期間記憶・維持され、肥満の発症・進展に関連することを初めて示した。乳児期のエピゲノム記憶が成人期の肥満のなりやすさに影響する分子機構の一つを明らかにした画期的な成果であると考えられる。将来の疾患の罹りやすさを予測して適切な介入により、疾患の発症が軽くなる理想的な医療が可能とされている。またCRISPR-dCas9-TET1CD系を用いた「エペゲノム編集」の研究は肝臓で脂質代謝遺伝子の働きを改善し、遺伝病や肝臓病などの治療への応用が期待される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (9 results)

All 2020 2019 2018 2017 Other

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

  • [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
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Upregulation of cancer-associated gene expression in activated fibroblasts in a mouse model of non-alcoholic steatohepatitis2019

    • Author(s)
      Asakawa M, Itoh M, Suganami T, Sakai T, Kanai S, Shirakawa I, Yuan X, Hatayama T, Shimada S, Akiyama Y, Fujiu K, Inagaki Y, Manabe I, Yamaoka S, Yamada T, Tanaka S, Ogawa Y.
    • Journal Title

      Sci Rep.

      Volume: 9 Issue: 1 Pages: 19601-19601

    • DOI

      10.1038/s41598-019-56039-0

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood2018

    • Author(s)
      X Yuan, K Tsujimoto, K Hashimoto, K Kawahori, N Hanzawa, M Hamaguchi, T Seki, M Nawa, T Ehara, Y Kitamura, I Hatada, M Konishi, N Itoh, Y Nakagawa, H Shimano, T Takai-Igarashi, Y Kamei, Y Ogawa.
    • Journal Title

      Nature Communications

      Volume: 9 Issue: 1 Pages: 636-636

    • DOI

      10.1038/s41467-018-03038-w

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mild maternal hypothyroxinemia during pregnancy induces persistent DNA hypermethylation in the hippocampal brain-derived neurotrophic factor gene in mouse offspring2018

    • Author(s)
      Kawahori K, Hashimoto K, Yuan X, Tsujimoto K, Hanzawa N, Hamaguchi M, Kase S, Fujita K, Tagawa K, Okazawa H, Nakajima Y, Shibusawa N, Yamada M, Ogawa Y
    • Journal Title

      Thyroid

      Volume: 28 Issue: 3 Pages: 395-406

    • DOI

      10.1089/thy.2017.0331

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Molecular Mechanism and Physiological Meaning of Epigenetic Regulation of FGF21 Gene Expression2019

    • Author(s)
      袁勲梅
    • Organizer
      7th International Conference on Food Factors
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] PGC1α欠損マウスを用いてDNA脱メチル化の網羅的解析2019

    • Author(s)
      袁勲梅
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] マウス乳仔期肝臓でのDNA脱メチル化における転写共役因子PGC1αの役割2018

    • Author(s)
      袁勲梅
    • Organizer
      第41回日本分子生物年会
    • Related Report
      2018 Research-status Report
  • [Presentation] FGF21遺伝子発現のエピゲノム制御:その分子機構と機能の意義2017

    • Author(s)
      袁勲梅
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
  • [Remarks]

    • URL

      http://www.tmd.ac.jp/grad/cme/member/personal/en.html

    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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