Elucidation of the Integrated Epigenomic Control Mechanisms by Metabolic Environment

• Project/Area Number: 20H03729
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Gunma University
• Principal Investigator: Inagaki Takeshi 群馬大学, 生体調節研究所, 教授 (10507825)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2020: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: エピゲノム / エピジェネティクス / 脂肪細胞分化 / ヒストン修飾

Outline of Research at the Start

本研究は、肥満や糖尿病と関係の深い脂肪細胞をモデルとして利用して実施する研究である。細胞内に存在する代謝物が、細胞内エネルギー環境を感知するセンサーとして働くという仮説に基づき、「代謝物によってエピゲノムが書き換えられることで、転写から翻訳までのセントラルドグマを一元的に制御する機構」の存在を予想して解明することを目指すものである。

Outline of Final Research Achievements

The epigenome, which senses metabolic environment, is involved in the control of cellular differentiation. Iron is essential for the activity of histone demethylase and DNA demethylase. In the process of adipocyte differentiation, we discovered that stored iron in cells is supplied by ferritinophagy. We also found that the iron chaperone PCBP migrates to the nucleus, and this plays a crucial role in adipocyte differentiation. Furthermore, after the induction of adipocyte differentiation, the activity of the histone demethylase JMJD1A and the DNA demethylase TET2 is regulated in an iron-dependent manner, leading to the rewriting of the epigenome. As a result, the expression of genes related to adipocyte differentiation is induced, and we elucidated the mechanism of adipocyte differentiation through this series of events.

Academic Significance and Societal Importance of the Research Achievements

肥満症や糖尿病の発症機序を理解するうえで、脂肪細胞の分化制御機構を解明することは重要である。今回、脂肪細胞分化にかかわるDNAメチル化やヒストンメチル化修飾といったエピゲノムの書き換えにおいて、鉄が重要な役割を果たすことを見出した。この新たな脂肪細胞分化の制御機構の提示は、肥満症や糖尿病の新しい治療戦略に寄与する可能性がある。

Research Products

• [Journal Article] T1R3 homomeric sweet taste receptor negatively regulates insulin-induced glucose transport through Gαs-mediated microtubules disassembly in 3T3-L1 adipocytes (2022)
  • Author(s): Masubuchi Yosuke、Ma Jinhui、Suzuki Tomohiro、Kojima Itaru、Inagaki Takeshi、Shibata Hiroshi
  • Journal Title: Endocrine Journal Volume: 69 Issue: 5 Pages: 487-493
  • DOI: 10.1507/endocrj.EJ21-0661
  • NAID: 130008118745
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Measurement of the nuclear concentration of α-ketoglutarate during adipocyte differentiation by using a fluorescence resonance energy transfer-based biosensor with nuclear localization signals (2021)
  • Author(s): Suzuki Tomohiro、Hayashi Mayuko、Komatsu Tetsuro、Tanioka Akiko、Nagasawa Masahiro、Tanimura-Inagaki Kyoko、Rahman Mohammad Sharifur、Masuda Shinnosuke、Yusa Kosuke、Sakai Juro、Shibata Hiroshi、Inagaki Takeshi
  • Journal Title: Endocrine Journal Volume: 68 Issue: 12 Pages: 1429-1438
  • DOI: 10.1507/endocrj.EJ21-0255
  • NAID: 130008136509
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bacteroides spp. promotes branched-chain amino acid catabolism in brown fat and inhibits obesity (2021)
  • Author(s): Yoshida Naofumi、Yamashita Tomoya、Osone Tatsunori、Shinohara Masakazu、Kitahama Seiichi、Sasaki Kengo、Sasaki Daisuke、Emoto Takuo、Saito Yoshihiro、Kitaura Yasuyuki、Shimomura Yoshiharu、Kondo Akihiko、Kajimura Shingo、Inagaki Takeshi、Yamada Takuji、Hirata Ken-ichi
  • Journal Title: iScience Volume: 24 Issue: 11 Pages: 103342-103342
  • DOI: 10.1016/j.isci.2021.103342
  • NAID: 120007179184
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spatiotemporal dynamics of SETD5-containing NCoR-HDAC3 complex determines enhancer activation for adipogenesis (2021)
  • Author(s): Matsumura Y, Ito R, Yajima A, Yamaguchi R, Tanaka T, Kawamura T, Magoori K, Abe Y, Uchida A, Yoneshiro T, Hirakawa H, Zhang J, Arai M, Yang C, Yang G, Takahashi H, Fujihashi H, Nakaki R, Yamamoto S, Ota S, Tsutsumi S, Inoue SI, Kimura H, Wada Y, Kodama T, Inagaki T, Osborne TF, Aburatani H, Node K, Sakai J.
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 7045-7045
  • DOI: 10.1038/s41467-021-27321-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ubiquitination-dependent and -independent repression of target genes by SETDB1 reveal a context-dependent role for its methyltransferase activity during adipogenesis (2021)
  • Author(s): Zhang J, Matsumura Y, Kano Y, Yoshida A, Kawamura T, Hirakawa H, Inagaki T, Tanaka T, Kimura H, Yanagi S, Fukami K, Doi T, Osborne TF, Kodama T, Aburatani H, Sakai J.
  • Journal Title: Genes Cells Volume: 26 Issue: 7 Pages: 513-529
  • DOI: 10.1111/gtc.12868
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PPARα activation directly upregulates thrombomodulin in the diabetic retina. (2020)
  • Author(s): Shiono A, Sasaki H, Sekine R, Abe Y, Matsumura Y, Inagaki T, Tanaka T, Kodama T, Aburatani H, Sakai J, Takagi H.
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 10837-10837
  • DOI: 10.1038/s41598-020-67579-1
  • Peer Reviewed / Open Access
• [Presentation] 熱産生性脂肪のエピジェネティクス (2021)
  • Author(s): 稲垣 毅 、酒井寿郎
  • Organizer: 第64回日本糖尿病学会
  • Invited
• [Presentation] Epigenetic Regulation of Adipose Cell Fate and Function (2021)
  • Author(s): 稲垣 毅
  • Organizer: The 9th Seoul International Congress of Endocrinology and Metabolism in conjunction with the 40th Annual Scientific Meeting of the Korean Endocrine Society (SICEM 2021)
  • Int'l Joint Research / Invited
• [Presentation] アドレナリンシグナルと熱産生性脂肪のepigenetics (2020)
  • Author(s): 稲垣 毅 、酒井寿郎
  • Organizer: 第93回日本内分泌学会学術総会
  • Invited
• [Presentation] 栄養と外部環境による脂肪のエピゲノム制御 (2020)
  • Author(s): 稲垣 毅
  • Organizer: 第105回 日本栄養食糧学会関東支部大会シンポジウム
  • Invited
• [Presentation] 脂肪細胞の性質を制御する環境記憶のエピジェネティクス (2020)
  • Author(s): 稲垣 毅
  • Organizer: 第41回日本肥満学会シンポジウム
  • Invited
• [Remarks] 群馬大学生体調節研究所
  • URL: https://www.imcr.gunma-u.ac.jp
• [Remarks] 群馬大学生体調節研究所代謝エピジェネティクス分野
  • URL: https://epigenetics.imcr.gunma-u.ac.jp
• [Remarks] 群馬大学生体調節研究所
  • URL: https://www.imcr.gunma-u.ac.jp/
• [Remarks] 群馬大学生体調節研究所代謝エピジェネティクス分野
  • URL: https://epigenetics.imcr.gunma-u.ac.jp/