Elucidation of a novel posttranscriptional mechanism regulating early lymphopoiesis

• Project/Area Number: 18K15185
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Kyoto University
• Principal Investigator: Uehata Takuya 京都大学, 医学研究科, 助教 (50785970)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 転写後制御 / mRNA分解 / 造血幹細胞 / 細胞系譜決定 / lineage priming / lineage bias / RNA分解 / single cell RNA seq / リンパ球初期分化 / RNA結合タンパク質

Outline of Final Research Achievements

In this study, we discovered a novel mechanism of how mRNA decay factors, Regnase-1 (Reg1) and Reg3 determine cell fate in bone marrow hematopoiesis. Analyses of mice lacking Reg1/3 revealed that Reg1/3 are essential for early-stage lymphopoiesis. Single cell RNA-seq of hematopoietic progenitors showed that Reg1/3 ensure lymphoid-lineage bias to maintain balanced hematopoiesis. Among mRNAs targeted by Reg1/3, Nfkbiz was identified as a critical regulator for suppressing lymphopoiesis and promotion of myelopoiesis in hematopoietic progenitors. Inflammatory signals, such as LPS, unleashed Nfkbiz expression due to downregulation of these RNases, resulting in initiation of emergency myelopoiesis. Collectively, we demonstrated that the Reg1/3-Nfkbiz axis acts as a novel rheostat that controls lineage priming in hematopoietic progenitors.

Academic Significance and Societal Importance of the Research Achievements

近年、造血幹細胞を含む多能性前駆細胞の遺伝子発現パターンには高度の多様性が存在し、これと一致するように分化バイアスが存在することが示唆されているが、その制御メカニズムは未解明であった。本研究において、転写因子やエピジェネティクスによる既存のメカニズムに加え、新たな制御相としてReg1/3-Nfkbiz制御軸が造血前駆細胞における分化バイアスの調節に重要な役割を果たしていることを世界で初めて見出した。本研究成果は、慢性炎症における造血障害や白血病などに対する新たな治療戦略への展開が期待できる。

Research Products

• [Int'l Joint Research] Weizmann Institute of Science(イスラエル)
• [Journal Article] RNA Recognition and Immunity?Innate Immune Sensing and Its Posttranscriptional Regulation Mechanisms (2020)
  • Author(s): Uehata Takuya、Takeuchi Osamu
  • Journal Title: Cells Volume: 9 Issue: 7 Pages: 1701-1701
  • DOI: 10.3390/cells9071701
  • Peer Reviewed / Open Access
• [Journal Article] The transcription factor E2A activates multiple enhancers that drive Rag expression in developing T and B cells (2020)
  • Author(s): Miyazaki Kazuko、Watanabe Hitomi、Yoshikawa Genki、Chen Kenian、Hidaka Reiko、Aitani Yuki、Osawa Kai、Takeda Rie、Ochi Yotaro、Tani-ichi Shizue、Uehata Takuya、Takeuchi Osamu、Ikuta Koichi、Ogawa Seishi、Kondoh Gen、Lin Yin C.、Ogata Hiroyuki、Miyazaki Masaki
  • Journal Title: Science Immunology Volume: 5 Issue: 51 Pages: 1455-1455
  • DOI: 10.1126/sciimmunol.abb1455
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] NET-CAGE characterizes the dynamics and topology of human transcribed cis-regulatory elements (2019)
  • Author(s): Hirabayashi Shigeki、Bhagat Shruti、Matsuki Yu、Takegami Yujiro、Uehata Takuya、Kanemaru Ai、Itoh Masayoshi、Shirakawa Kotaro、Takaori-Kondo Akifumi、Takeuchi Osamu、Carninci Piero、Katayama Shintaro、Hayashizaki Yoshihide、Kere Juha、Kawaji Hideya、Murakawa Yasuhiro
  • Journal Title: Nature Genetics Volume: 51 Issue: 9 Pages: 1369-1379
  • DOI: 10.1038/s41588-019-0485-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Translation-dependent unwinding of stem?loops by UPF1 licenses Regnase-1 to degrade inflammatory mRNAs (2019)
  • Author(s): Mino Takashi、Iwai Noriki、Endo Masayuki、Inoue Kentaro、Akaki Kotaro、Hia Fabian、Uehata Takuya、Emura Tomoko、Hidaka Kumi、Suzuki Yutaka、Standley Daron M、Okada-Hatakeyama Mariko、Ohno Shigeo、Sugiyama Hiroshi、Yamashita Akio、Takeuchi Osamu
  • Journal Title: Nucleic Acids Research Volume: 47 Pages: 8838-8859
  • DOI: 10.1093/nar/gkz628
  • NAID: 120006708220
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation. (2019)
  • Author(s): Yamasoba D, Sato K, Ichinose T, Imamura T, Koepke L, Joas S, Reith E, Hotter D, Misawa N, Akaki K, Uehata T, Mino T, Miyamoto S, Noda T, Yamashita A, Standley DM, Kirchhoff F, Sauter D, Koyanagi Y, Takeuchi O.
  • Journal Title: Nat Microbiol Volume: 4 Issue: 9 Pages: 1532-1544
  • DOI: 10.1038/s41564-019-0460-3
  • NAID: 120006731123
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pulmonary Regnase-1 orchestrates the interplay of epithelium and adaptive immune systems to protect against pneumonia (2018)
  • Author(s): Nakatsuka Yoshinari、Vandenbon Alexis、Mino Takashi、Yoshinaga Masanori、Uehata Takuya、Cui Xiaotong、Sato Ayuko、Tsujimura Tohru、Suzuki Yutaka、Sato Atsuyasu、Handa Tomohiro、Chin Kazuo、Sawa Teiji、Hirai Toyohiro、Takeuchi Osamu
  • Journal Title: Mucosal Immunology Volume: AOP Issue: 4 Pages: 1203-1218
  • DOI: 10.1038/s41385-018-0024-5
  • Peer Reviewed / Int'l Joint Research
• [Presentation] LYMPHOID-MYELOID CELL FATE DETERMINATION BY ENDORIBONUCLEASES REGNASE-1 AND -3 (2020)
  • Author(s): Takuya Uehata, Shinnosuke Yamada, Masaki Miyazaki, Amir Giladi, Alexis Vandenbon, Ido Amit, Hiroshi Kawamoto, and Osamu Takeuchi
  • Organizer: 8th Annual Meeting of the International Cytokine & Interferon Society
  • Int'l Joint Research
• [Presentation] Critical Roles of Endonucleases Regnase-1 and Regnase-3 in Early Lymphopoiesis (2019)
  • Author(s): Takuya Uehata
  • Organizer: Keystone symposia
  • Int'l Joint Research
• [Presentation] Critical roles of endonucleases Regnase-1 and Regnase-3 in early lymphopoiesis (2019)
  • Author(s): Takuya Uehata
  • Organizer: 17th International Congress of Immunology
  • Int'l Joint Research
• [Presentation] Endonucleases Regnase-1 and Regnase-3 regulate transcriptome biases to ensure lymphopoiesis (2019)
  • Author(s): Takuya Uehata, Shinnosuke Yamada, Masaki Miyazaki, Amir Giladi, Alexis Vandenbon, Ido Amit, Hirohi Kawamoto and Osamu Takeuchi
  • Organizer: CiRA 2019 International Symposium
  • Int'l Joint Research
• [Presentation] 免疫細胞を制御するRNA結合タンパク質の機能解析 (2019)
  • Author(s): 植畑拓也、山田信之輔、織大祐、今見考志、宮崎正輝、石濱泰、河本宏、竹内理
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Ribonuclease Regnase-1 and Regnase-3 have a critical role in controlling transcriptome biases in LMPP to ensure lymphopoiesis (2019)
  • Author(s): Shinnosuke Yamada, Daisuke Ori, Masaki Miyazaki, Takuya Uehata, Osamu Takeuchi
  • Organizer: The 48th Annual Meeting of The Japanese Society for Immunology
• [Presentation] Critical Roles of Endonucleases Regnase-1 and Regnase-3 in Early Lymphopoiesis (2019)
  • Author(s): Takuya Uehata
  • Organizer: Keystone symposia, Transcription and RNA Regulation in Inflammation and Immunity
  • Int'l Joint Research
• [Presentation] Regnase-1 and Regnase-3 regulate cell fate of early lymphoid progenitors in the bone marrow (2018)
  • Author(s): 植畑拓也
  • Organizer: 第４７回日本免疫学会学術集会
• [Book] 生化学 (2018)
  • Author(s): 植畑 拓也、竹内 理
  • Total Pages: 10
  • Publisher: 日本生化学会
• [Book] 医学のあゆみ (2018)
  • Author(s): 植畑 拓也、竹内 理
  • Total Pages: 7
  • Publisher: 医歯薬出版