Regulatory mechanism of beige adipocyte-differentiation by protein phosphatase.

• Project/Area Number: 19K17952
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Tohoku University
• Principal Investigator: Ito Ryo 東北大学, 医学系研究科, 助教 (80733815)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 熱産生 / エピゲノム / 脱リン酸化 / 遺伝子発現制御 / 脂肪細胞 / リン酸化 / プロテオミクス

Outline of Research at the Start

ベージュ脂肪細胞の分化には、βアドレナリン刺激によるエピゲノム変化を介した熱産生遺伝子の活性化が必要である。ヒストン脱メチル化酵素JMJD1Aはβアドレナリンシグナル下流でリン酸化され、抑制型ヒストンメチル化修飾を消去することでベージュ脂肪細胞を促進する。本研究では、JMJD1Aの脱リン酸化酵素複合体を明らかにし、白色脂肪のベージュ化におけるエピゲノム調節機構の解明を目指す。

Outline of Final Research Achievements

Beige adipocytes are attracting attention as a novel therapeutic target for lifestyle-related diseases because beige adipocyte burn sugar and fat actively. It has been shown that the histone demethylase JMJD1A is phosphorylated downstream of the β-adrenergic signal, removing the inhibitory histone methylation and activating chromatin. It was unclear how this phosphorylation level of JMJD1A was regulated. In this study, we comprehensively searched for JMJD1A interacting factors and identified a phospho JMJD1A protein phosphatase complex (p-JMJD1A-PPC). p-JMJD1A-PPC dephosphorylate phosphorylated JMJD1A and contributed to the regulation of the expression of thermogenic genes in beige adipocytes.

Academic Significance and Societal Importance of the Research Achievements

本研究では、ヒストン脱メチル化酵素JMJD1Aのリン酸化調節に着目し、脱リン酸化酵素を同定し、その脱リン酸化酵素を阻害することでJMJD1Aのリン酸化を亢進させ、ベージュ脂肪細胞分化を促進できることを明らかにした。すなわち、脱リン酸化酵素のコントロールを介してヒストン脱メチル化酵素による遺伝子発現を調節できることを示しており、この点に学術的意義がある。また、これらの成果は肥満や高脂血症といった生活習慣病に対する治療薬開発に貢献できると考えられる。

Research Products

• [Journal Article] Comparative proteomic analysis to identify the novel target gene of angiotensin II in adrenocortical H295R cells (2021)
  • Author(s): Ito Ryo、Shima Hiroki、Masuda Koji、Sato Ikuko、Shimada Hiroki、Yokoyama Atsushi、Shirahige Katsuhiko、Igarashi Kazuhiko、Sugawara Akira
  • Journal Title: Endocrine Journal Volume: 68 Issue: 4 Pages: 441-450
  • DOI: 10.1507/endocrj.EJ20-0144
  • NAID: 130008030764
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Discovery of a chemical compound that suppresses expression of BEX2, a dormant cancer stem cell-related protein (2021)
  • Author(s): Saijoh S, Nakamura-Shima M, Shibuya-Takahashi R, Ito R, Sugawara A, Yamazaki T, Imai T, Asada Y, Matsuura K, Iwai W, Wakui Y, Abue M, Kawamura S, Katayose Y, Fujimori H, Mochizuki M, Yasuda J, Yamaguchi K, Sugamura K,Satoh K, Katori Y, Tamai K.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 537 Pages: 132-139
  • DOI: 10.1016/j.bbrc.2020.11.022
  • Peer Reviewed
• [Journal Article] The establishment of a novel high-throughput screening system using RNA-guided genome editing to identify chemicals that suppress aldosterone synthase expression (2020)
  • Author(s): Ito R, Morita M, Nakano T, Sato I, Yokoyama A, Sugawara A
  • Journal Title: Biochem Biophys Res Commun Volume: 534 Pages: 672-679
  • DOI: 10.1016/j.bbrc.2020.11.020
  • Peer Reviewed
• [Journal Article] FABP7 Regulates Acetyl-CoA Metabolism Through the Interaction with ACLY in the Nucleus of Astrocytes (2020)
  • Author(s): Kagawa Y, Umaru BA, Shima H, Ito R, Zama R, Islam A, Kanno S, Yasui A, Sato S, Jozaki K, Shil SK, Miyazaki H, Kobayashi S, Yamamoto Y, Kogo H, Shimamoto-Mitsuyama C, Sugawara A, Sugino N, Kanamori M, Tominaga T, Yoshikawa T, Fukunaga K, Igarashi K, Owada Y
  • Journal Title: Molecular Neurobiology Volume: 57 Issue: 12 Pages: 4891-4910
  • DOI: 10.1007/s12035-020-02057-3
  • Peer Reviewed / Open Access / Int'l Joint Research