Chromatin remodeling factor ARIP4 regulates the cardiomyocyte differentiation

• Project/Area Number: 16K07254
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Molecular biology
• Research Institution: Osaka University
• Principal Investigator: TSUCHIYA Megumi 大阪大学, 生命機能研究科, 特任助教(常勤) (00390691)
• Research Collaborator: TAKEUCHI jun ; OGAWA hidesato ; HIRAOKA yasushi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 心筋分化誘導 / 心筋細胞 / クロマチン変換因子 / クロマチン構造変換 / 心筋緻密化障害 / マウスES細胞 / 発生・分化 / 転写因子 / クロマチン / 発現制御 / 細胞・組織

Outline of Final Research Achievements

In this study, we demonstrate that the chromatin remodeling factor, ARIP4 played an essential role for cardiomyocyte differentiation of mouse embryonic stem (ES) cells. The reducing of protein levels of ARIP4 or an ectopic expression of ATPase mutant of ARIP4 suppressed the ES differentiation to the cardiomyocyte. Interestingly, genome-wide analysis clearly showed that ARIP4 mainly localized near the promoter region and the region was inactivated through the ATPase activity of ARIP4. Furthermore, endogenous ARIP4 interacted with p62 in mice embryonic hearts. Since p62 is well known as a selective autophagy receptor, it is suggested that p62 monitors the cellular energy levels and regulates the protein levels of ARIP4 during the cardiomyocyte differentiation. These data strongly suggest that ARIP4 acts as a key regulator for the cardiomyocyte differentiation through the modulation of chromatin structure with monitoring the energy level during cell differentiation.

Academic Significance and Societal Importance of the Research Achievements

本研究による心筋分化過程の分子レベルでの解明は、心筋再生医療の発展に大きく貢献する。このような、細胞内のエネルギー状態をモニターするエピジェネティックなプロモーター制御の分子メカニズムの解明は、細胞内エネルギー代謝の変化に関わる遺伝子発現制御機構を理解するだけでなく、代謝経路が大きく変化する癌化のメカニズム解明のための極めて重要な手掛かりとなると考えられる。

Research Products

• [Journal Article] p62/SQSTM1 promotes rapid ubiquitin conjugation to target proteins after endosome rupture during xenophagy (2018)
  • Author(s): Tsuchiya Megumi、Ogawa Hidesato、Koujin Takako、Mori Chie、Osakada Hiroko、Kobayashi Shouhei、Hiraoka Yasushi、Haraguchi Tokuko
  • Journal Title: FEBS Open Bio Volume: 8 Issue: 3 Pages: 470-480
  • DOI: 10.1002/2211-5463.12385
  • Peer Reviewed / Open Access
• [Journal Article] Ad4BP/SF-1 regulates cholesterol synthesis to boost the production of steroids (2018)
  • Author(s): Takashi Baba, Hiroyuki Otake, Miki Inoue, Tetsuya Sato, Yasuhiro Ishihara, Ju-Yeon Moon, Megumi Tsuchiya, Kanako Miyabayashi, Hidesato Ogawa, Yuichi Shima, Lixiang Wang, Ryuichiro Sato, Takeshi Yamazaki, Mikita Suyama, Masatoshi Nomura, Man Ho Choi, Yasuyuki Ohkawa & Ken-ichirou Morohashi
  • Journal Title: Communications Biology Volume: 1 Issue: 1 Pages: 1-9
  • DOI: 10.1038/s42003-018-0020-z
  • NAID: 120006799378
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ess2 bridges transcriptional regulators and spliceosomal complexes via distinct interacting domains (2018)
  • Author(s): Ichiro Takada, Megumi Tsuchiya, Kaori Yanaka, Shinya, Hidano, Sayuri Takahashi, Takashi Kobayashi, Hidesato Ogawa, Sinichi Nakagawa, Makoto Makishima
  • Journal Title: Biochem Biophys Res Commun. Volume: 497 Issue: 2 Pages: 597-604
  • DOI: 10.1016/j.bbrc.2018.02.110
  • Peer Reviewed / Open Access
• [Journal Article] A protein preparation method for the high-throughput identification of proteins interacting with a nuclear cofactor using LC-MS/MS analysis. (2017)
  • Author(s): Tsuchiya M, Karim M. R, Matsumoto T, *Ogawa H, *Taniguchi H
  • Journal Title: J. Vis. Exp Volume: 119 Issue: 119
  • DOI: 10.3791/55077
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Lysosomal activity maintains glycolysis and cyclin E1 expression by mediating Ad4BP/SF-1 stability for proper steroidogenic cell growth (2017)
  • Author(s): Syu JS, Baba T, Huang JY, Ogawa H, Hsieh CH, Hu JX, Chen TY, Lin TC, Tsuchiya M, Morohashi K, Huang BM, Lu FI
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 240-240
  • DOI: 10.1038/s41598-017-00393-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression analysis of Baf60c during heart regeneration in axolotls and neonatal mice. (2016)
  • Author(s): Nakamura R, Koshiba-T K, Tsuchiya M, Kojima M, Ogawa H, and Takeuchi-K J
  • Journal Title: Development Growth and Differentiation Volume: 58 Issue: 4 Pages: 367-382
  • DOI: 10.1111/dgd.12281
  • Peer Reviewed
• [Journal Article] Depletion of autophagy receptor p62/SQSTM1 enhances the efficiency of gene delivery in mammalian cells. (2016)
  • Author(s): Tsuchiya M, Ogawa H, Koujin T, Kobayashi S, Mori C, Hiraoka Y, Haraguchi T.
  • Journal Title: FEBS letters. Volume: 590 Issue: 16 Pages: 2671-2680
  • DOI: 10.1002/1873-3468.12262
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Depletion of autophagy receptor p62/SQSTM1 enhances the efficiency of gene delivery in mammalian cells (2018)
  • Author(s): Hidesato Ogawa, Megumi Tsuchiya, Takako Koujin, Chie Mori, Hiroko Osakada, Kento Watanabe, Shouhei Kobayashi, Yasushi Hiraoka, Tokuko Haraguchi
  • Organizer: 第70回細胞生物第51回発生生物合同大会
• [Presentation] オートファジーレセプターp62/SQSTM1 を標的とした効果的な遺伝子導入法の確立 (2018)
  • Author(s): 土屋 惠, 小川英知, 渡邊 賢人,荒神 尚子, 小林 昇平, 森 知栄, 小坂田 裕子, 平岡 泰, 原口 徳子
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Depletion of autophagy receptor p62/SQSTM1 enhances the efficiency of gene delivery in mammalian cells (2017)
  • Author(s): Hidesato Ogawa, Megumi Tsuchiya, Takako Koujin, Shouhei Kobayashi, Chie Mori, Yasushi Hiraoka, Tokuko Haraguchi
  • Organizer: 第69回日本細胞生物学会大会
• [Presentation] Depletion of autophagy receptor p62/SQSTM1 enhances the efficiency of gene delivery in mammalian cells (2017)
  • Author(s): Megumi Tsuchiya, Hidesato Ogawa, Takako Koujin, Shouhei Kobayashi, Chie Mori, Hiroko Osakada, Yasushi Hiraoka, Tokuko Haraguchi
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] オートファジーレセプターp62/SQSTM1 の細胞内タ ン パク質量の調節による効果的な遺伝子導入法の確立 (2016)
  • Author(s): 土屋 惠, 小川 英知, 荒神 尚子, 小林 昇平 , 森 知栄 , 平岡 泰, 原口 徳子
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜, 横浜市
  • Year and Date: 2016-11-30
• [Remarks] 大阪大学大学院生命機能研究科細胞核ダイナミクス研究室ホームページ
  • URL: http://www.fbs.osaka-u.ac.jp/labs/hiraoka/index.html