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熱産生脂肪細胞を誘導するエピゲノム酵素リン酸化スイッチの解明

Publicly Offered Research

Project AreaIntegrative understanding of biological phenomena with temperature as a key theme
Project/Area Number 18H04688
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Research InstitutionThe University of Tokyo

Principal Investigator

酒井 寿郎  東京大学, 先端科学技術研究センター, 教授 (80323020)

Project Period (FY) 2018-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Keywordsベージュ脂肪細胞 / アドレナリンシグナル / ヒストン脱メチル化酵素 / 細胞記憶 / 脱リン酸化酵素タンパク質複合体
Outline of Annual Research Achievements

(A)白色脂肪組織のベージュ化を担うヒストン脱メチル化酵素JMJD1Aの265番目のセリン残基リン酸化の脱リン酸化酵素の同定を試み、① 3T3-L1白色脂肪前駆細胞でJMJD1Aプロテオームを解析し、触媒サブユニットPP1βとミオシン軽鎖ホスファターゼの調節サブユニットMYPT1とを同定。② プロテオミクス解析よりMYPT1がβアドレナリン受容体シグナル依存的にJMJD1Aと相互作用する知見を得た。
(B)ロシグリタゾン(核内受容体PPARγのアゴニスト)添加によりベージュ化を誘導する系で、MYPT1、PP1βがベージュ化を抑制することを見出した。① 野生型マウス由来の皮下白色脂肪初代培養細胞において、MYPT1またはPP1βをノックダウンすることにより熱産生遺伝子群の(Ucp1など)発現が増加した。② MYPT1flox/floxマウス由来の皮下白色脂肪初代培養細胞に、Creリコンビナーゼのアデノウイルスを感染させMYPT1遺伝子を欠損させることでも同様に知見が得られた。
(C)MYPT1はJMJD1AおよびJMJD1A以外の標的を介してベージュ化を抑制 ① MYPT1のノックダウンで、不死化前駆 白色脂肪細胞のJMJD1Aの265番目のセリン残基リン酸化レベルが増加した。② S265A-JMJD1A点変異マウス由来の初代 皮下白色脂肪培養細胞でMYPT1ノックダウンにより、野生型に比べ、点変異マウス由来のベージュ細胞では、Ucp1の発現誘導は低下していた。
(D)MYPT1が標的とするリン酸化タンパク質の網羅的な同定。
MYPT1をノックダウンした不死化白色脂肪前駆細胞からリン酸化ペプチドを濃縮・精製し、リン酸化プロテオミクス解析の結果、MYPT1ノックダウンにより、リン酸化ペプチドの数が増加するMYPT1の脱リン酸化標的タンパク質を網羅的に同定する事に成功した。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (14 results)

All 2019 2018 Other

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (10 results) (of which Int'l Joint Research: 6 results,  Invited: 10 results) Remarks (1 results)

  • [Journal Article] Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT22019

    • Author(s)
      Osawa T, Shimamura T, Saito K, Hasegawa Y, Ishii N, Nishida M, Ando R, Kondo A, Anwar M, Kato K, Endo K, Yamano S, Kanki Y, Matsumura Y, Minami T, Tanaka T, Anai M, Wada Y, Wanibuchi H, Hayashi M, Hamada A, Yoshida M, Yachida S, Nakao M, Sakai J, Aburatani H, Shibuya M, Hanada K, Miyano S, Soga T, Kodama T
    • Journal Title

      Cell Rep.

      Volume: 29(1) Issue: 1 Pages: 89-103

    • DOI

      10.1016/j.celrep.2019.08.087

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gene Expression Profiles Induced by a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα) Pemafibrate2019

    • Author(s)
      Sasaki Y, Raza-Iqbal S, Tanaka T, Murakami K, Anai M, Osawa T, Matsumura Y, Sakai J, Kodama T
    • Journal Title

      Int J Mol Sci

      Volume: 20(22) Issue: 22 Pages: 5682-5682

    • DOI

      10.3390/ijms20225682

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition2018

    • Author(s)
      Nagai Nao、Ohguchi Hiroto、Nakaki Ryo、Matsumura Yoshihiro、Kanki Yasuharu、Sakai Juro、Aburatani Hiroyuki、Minami Takashi
    • Journal Title

      PLOS Genetics

      Volume: 14 Issue: 11 Pages: e1007826-e1007826

    • DOI

      10.1371/journal.pgen.1007826

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] “Histone demethylase-mediated adaptive thermogenesis”2019

    • Author(s)
      Juro Sakai
    • Organizer
      71th Annual Korean Physiological Society Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 内分泌機構におけるエピゲノム2019

    • Author(s)
      酒井 寿郎
    • Organizer
      第92回日本内分泌学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 脂肪細胞の機能制御に関わるヒストン修飾とクロマチン構造の変化2019

    • Author(s)
      酒井 寿郎
    • Organizer
      第42回日本分子生物学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] JMJD1A mediates acute and chronic thermogenic responses through complementary mechanisms2019

    • Author(s)
      Juro Sakai
    • Organizer
      The 9th Federation of Asian and Oceanian Physiological Societies Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ヒストン脱メチル化酵素による寒冷環境への適応機構2018

    • Author(s)
      酒井寿郎
    • Organizer
      第91回日本内分泌学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Histone demethylates JMJD1A coordinates acute and chronic adaptation to cold stress via thermogenic phosphor-switch.2018

    • Author(s)
      酒井寿郎
    • Organizer
      第50回日本動脈硬化学会総会・学術集会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Beta-Adrenergic Signaling Regulates a Concerted Thrmogenic Tesponse in Brown Adipose Tissue and subcutaneous White Adipose Tissue2018

    • Author(s)
      Juro Sakai
    • Organizer
      American Diabetes Association 77th Scientific Sessions
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] JMJD1A Mediates Acute and Chronic Thermogenic Responses through Complementary Mechanisms2018

    • Author(s)
      Juro Sakai
    • Organizer
      The 5th Bandung International Biomoleculara Medicine Conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] JMJD1A Mediates Acute and Chronic Thermogenic Responses through Complementary Mechanisms2018

    • Author(s)
      Juro Sakai
    • Organizer
      THE 15TH NIKKO INTERNATIONAL SYMPOSIUM 2018 Genomic Approach for Non-communicable Diseases
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] A histone demethylase JMJD1A mediates acute and chronic thermogenic responses through complementary Mechanisms2018

    • Author(s)
      Juro Sakai
    • Organizer
      The 4th IMCR Symposium on Endocrine and Metabolism: At the Cutting Edge of Metabolic Regulation Research
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Remarks] 東京大学先端科学技術研究センター酒井研究室/原著論文

    • URL

      http://www.mm.rcast.u-tokyo.ac.jp/publications/pubs.html

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report

URL: 

Published: 2018-04-23   Modified: 2021-01-27  

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