| Project/Area Number |
18K15185
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 49070:Immunology-related
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| Research Institution | Kyoto University |
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Principal Investigator |
Uehata Takuya 京都大学, 医学研究科, 助教 (50785970)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥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)
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| 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 |
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| 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.
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| 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。
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