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

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K01840
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: Tokyo 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
• Keywords: PPARα / FGF21 / DNAメチル化 / エピジェネティクス / DOHaD

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.

Free Research Field

応用健康科学

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。