2022 Fiscal Year Final Research Report
Elucidation of the mechanism of beiging through identification of phosphatase of histone demethylase JMJD1A
Project/Area Number |
21K21211
|
Research Category |
Grant-in-Aid for Research Activity Start-up
|
Allocation Type | Multi-year Fund |
Review Section |
0909:Sports sciences, physical education, health sciences, and related fields
|
Research Institution | Tohoku University |
Principal Investigator |
|
Project Period (FY) |
2021-08-30 – 2023-03-31
|
Keywords | エピゲノム / ベージュ脂肪細胞 / 脱リン酸化酵素 |
Outline of Final Research Achievements |
Beige adipocytes are thermogenic adipocytes induced in white fat by chronic cold exposure and are attracting attention as a novel strategy for the treatment and prevention of obesity. In this study, we identified MYPT1-PP1β as a phosphatase of JMJD1A, a histone demethylase crucial for beiging, and found that their activity is inhibited via PKA-dependent phosphorylation, increasing phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1β depletion results in JMJD1A-mediated H3K9 demethylation and activation of Ucp1 gene. In addition, MYPT1-PP1β suppresses beiging by dephosphorylating myosin light chain which regulates actomyosin tension-mediated activation of YAP/TAZ. Pre-adipocyte specific Mypt1 deficient mice exhibit enhanced beiging, improved die-induced obesity, and glucose metabolism. Thus, we have uncovered regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of transcriptional co-activators.
|
Free Research Field |
代謝学
|
Academic Significance and Societal Importance of the Research Achievements |
本研究成果は、肥満や肥満が成因基盤とする生活習慣病の治療・予防法への応用が期待される。本研究は、先行研究で同定した寒冷刺激を感知しベージュ化を誘導するエピゲノム酵素のリン酸化に着目し、このリン酸化 レベルを制御することでエピゲノム書き換えを誘導し、「脂肪燃焼体質」を細胞に記憶させることができるか検証する挑戦的な試みであった。エピゲノム酵素の機能を亢進させ、エピゲノム変化を特定の遺伝子座で制御するという新規エピゲノム創薬の可能性を提示するもので、今後生命科学および多因子性疾患の予防と治療に大きな可能性が広がることが期待される。
|