| Project/Area Number |
17K09899
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Chiba University |
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Principal Investigator |
Takayama Naoya 千葉大学, 大学院医学研究院, 講師 (10584229)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | ヒト造血幹細胞 / クロマチン / CTCF / オープンクロマチン解析 / 静止期 / エピゲノム解析 / エピゲノム |
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| Outline of Final Research Achievements |
Human Long Term-hematopoietic stem cells (LT-HSC) is required for life-long blood production. Though both LT-HSC and the Short Term (ST)-HSC that lie immediately downstream are capable of multilineage repopulation, only LT-HSC possess sufficient capacity for self-renewal. As few transcriptional changes underlie this transition, we used ATAC-seq on human stem/progenitor subsets (HSPC) to uncover unique chromatin accessibility signatures (Act/HSPC signature), which discriminate LT-HSC and other progenitors. The Act/HSPC signature contains CTCF binding sites mediating chromatin interactions, engaged in ST-HSC but not LT-HSC, enclosing multiple stemness pathway genes active in LT-HSC and repressed in ST-HSC. CTCF silencing derepressed stemness genes and inhibited the transition from quiescent LT-HSC to activated ST-HSC.
Hence, 3D chromatin mediator, CTCF, endow a new gatekeeper function that governs the disparate stemness pathways linked to quiescence and self-renewal in HSC.
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| Academic Significance and Societal Importance of the Research Achievements |
高い自己複製能を持つ造血幹細胞は、造血幹細胞移植など再生医療へ広く応用可能であるが、深刻なドナー不足は解決の目処がたっていない。その解決策として、HSC固有の能力である自己複製機構を正しく理解し、自己複製能を維持したまま増幅できる培養系の確立が必要である。
本研究では、最新の血液細胞識別法を用いてヒト臍帯血由来血液細胞を高純化し、最新のエピゲノム解析を駆使することで、造血幹細胞の自己複製能に直結する静止期離脱機構にCTCFを介したゲノムの3次元構造の変化が必須であることを世界に先駆けて明らかにした。
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