Posttranscriptional regulation of iron metabolism via RNA methylation

• Project/Area Number: 20K22737
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0802:Biomedical structure and function and related fields
• Research Institution: Kyoto University
• Principal Investigator: Yoshinaga Masanori 京都大学, 医学研究科, 助教 (70878347)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: RNA修飾 / 鉄代謝 / 赤芽球分化 / CRISPRスクリーニング

Outline of Research at the Start

近年RNA上に付加された修飾が転写後調節に重要な役割を果たすことが認識されるようになってきたが、鉄代謝における役割は未だ不明である。本研究では、申請者が独自に実施したCRISPRスクリーニングにより同定されたRNA修飾酵素の遺伝子改変マウスを解析することにより、鉄代謝制御におけるRNA修飾の役割の解明を目指す。

Outline of Final Research Achievements

In this study, we investigated the roles of a novel RNA m6A methyltransferase METTL16 in the regulation of iron metabolism. We revealed that the mice that lack METTL16 specifically in erythroblasts lead to embryonic death due to severe anemia. Moreover, METTL16-deficient erythroblasts failed to express erythroid transcription factors GATA-1 and KLF1, and iron-related genes including transferrin receptor. Next, we investigated the molecular mechanisms that act downstream of METTL16 and revealed that MTR4-nuclear exosome is critically involved in the mRNA regulation mediated by METTL16. These findings establish the novel mechanisms of gene expression of iron-regulatory transcripts mediated by METTL16.

Academic Significance and Societal Importance of the Research Achievements

本研究により、これまで不明であったMETTL16の生体における機能の一端が解明された。また、METTL16の下流で作用する分子機構を網羅的に探索し、はじめてm6A修飾とMTR4-核内エクソソームの関係性を明らかにした。本研究成果は貧血をはじめとする鉄代謝異常や造血器疾患の病態の理解に寄与すると考えられる。

Research Products

• [Int'l Joint Research] スタンフォード大学(米国)
• [Int'l Joint Research] スタンフォード大学(米国)
• [Journal Article] Cyclin J-CDK complexes limit innate immune responses by reducing proinflammatory changes in macrophage metabolism (2022)
  • Author(s): Chong Yee Kien、Tartey Sarang、Yoshikawa Yuki、Imami Koshi、Li Songling、Yoshinaga Masanori、Hirabayashi Ai、Liu Guohao、Vandenbon Alexis、Hia Fabian、Uehata Takuya、Mino Takashi、Suzuki Yutaka、Noda Takeshi、Ferrandon Dominique、Standley Daron M.、Ishihama Yasushi、Takeuchi Osamu
  • Journal Title: Science Signaling Volume: 15 Issue: 729 Pages: 1-19
  • DOI: 10.1126/scisignal.abm5011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TANK prevents IFN-dependent fatal diffuse alveolar hemorrhage by suppressing DNA-cGAS aggregation (2021)
  • Author(s): Wakabayashi Atsuko、Yoshinaga Masanori、Takeuchi Osamu
  • Journal Title: Life Science Alliance Volume: 5 Issue: 2 Pages: e202101067-e202101067
  • DOI: 10.26508/lsa.202101067
  • Peer Reviewed / Open Access
• [Journal Article] Profibrotic function of pulmonary group 2 innate lymphoid cells is controlled by regnase-1 (2020)
  • Author(s): Nakatsuka Yoshinari、Yaku Ai、Handa Tomohiro、Vandenbon Alexis、Hikichi Yuki、Motomura Yasutaka、Sato Ayuko、Yoshinaga Masanori、Tanizawa Kiminobu、Watanabe Kizuku、Hirai Toyohiro、Chin Kazuo、Suzuki Yutaka、Uehata Takuya、Mino Takashi、Tsujimura Tohru、Moro Kazuyo、Takeuchi Osamu
  • Journal Title: European Respiratory Journal Volume: 57 Issue: 3 Pages: 2000018-2000018
  • DOI: 10.1183/13993003.00018-2020
  • Peer Reviewed
• [Journal Article] がん免疫療法における免疫チェックポイント機構とマクロファージのはたらき (2020)
  • Author(s): 吉永正憲, 竹内理
  • Journal Title: Trends in Cancer Immunology Volume: 3 Pages: 3-5
• [Presentation] 赤芽球分化を制御する新規転写後調節機構の解明 (2021)
  • Author(s): 吉永正憲、竹内理
  • Organizer: 第44回日本分子生物学年会
• [Presentation] Manipulation of Regnase-1 mRNA stability by antisense oligonucleotides alleviates inflammatory responses in pulmonary and autoimmune diseases (2021)
  • Author(s): Ka Man Tse, Xiaotong Cui, Alexis Vandenbon, Keiko Yasuda, Takuya Uehata, Ayuko Sato, Tohru Tsujimura, Masanori Yoshinaga, Tatsusada Okuno, Yoshinari Nakatsuka, Osamu Takeuchi
  • Organizer: KAI International Meeting 2021
  • Int'l Joint Research
• [Presentation] Manipulation of Regnase-1 mRNA stability by morpholino-based antisense oligonucleotides alleviates inflammatory responses in pulmonary and autoimmune diseases (2021)
  • Author(s): Ka Man Tse, Xiaotong Cui, Alexis Vandenbon, Keiko Yasuda, Takuya Uehata, Ayuko Sato, Tohru Tsujimura, Takashi Mino, Masanori Yoshinaga, Tatsusada Okuno, Yoshinari Nakatsuka, Osamu Takeuchi
  • Organizer: 第22回日本RNA学会年会
• [Presentation] Manipulating the expressions of Regnase-1 by stem-loop-targeting-antisense oligonucleotides to counteract inflammatory diseases (2021)
  • Author(s): Ka Man Tse, Xiaotong Cui, Alexis Vandenbon, Takashi Mino, Takuya Uehata, Keiko Yasuda, Ayuko Sato, Tohru Tsujimura, Fabian Hia, Masanori Yoshinaga, Osamu Takeuchi
  • Organizer: 第44回日本分子生物学年会
• [Presentation] Analysis of metabolic reprogramming in macrophage utilizing genome-wide CRISPR screening (2021)
  • Author(s): Shota Yasukura, Masanori Yoshinaga, Michael C Bassik, Osamu Takeuchi
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] Identification of novel regulators of erythroid differentiation via genome-wide CRISPR screen (2020)
  • Author(s): 吉永正憲, 竹内理
  • Organizer: 第１回医薬系研究交流サロン