Epigenetic regulation of hematopoietic stem cell self renewal
| Project/Area Number |
18390277
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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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 |
IWAMA Atsushi Chiba University, Graduate School of Medicine, Professor (70244126)
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| Co-Investigator(Kenkyū-buntansha) |
CHIBA Tetsuhiro Chiba University, Graduate School of Medicine, Assistant Professor (00381583)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥17,750,000 (Direct Cost: ¥15,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2007: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2006: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | polycomb group gene / hematopoietic stem cell / self-renewal / Bmil / Dmap1 |
|---|
| Research Abstract |
The polycomb group (PcG) protein Bmi1 plays an essential role in both self-renewal of adult HSCs and development of their bone marrow (BM) microenvironment. Derepression of the Ink4a/Arf gene locus has been largely attributed to the defects in HSCs, but not in BM microenvironment in Bmi1-deficient mice. In respect of HSC differentiation, Bmi1-deficient mice display a severe defect in lymphocyte development, but the underlying mechanisms remained unclear. In this study, we analyzed lymphopoiesis in Bmi1-/- Ink4a-Arf/- mice. Deletion of the Ink4a and Arf genes did not rescue a differentiation block at pre-B cell stage in Bmi1-deficient mice. When Bmi1-/- Ink4a-Arf/- BM cells were transplanted into wild-type recipients, however, Bmi1-/- Ink4a Arf/- cells normally differentiated into mature B cells, and generated a significantly increased number of common lymphoid progenitors and pre-B cells. Conversely, B-cell differentiation was arrested when the wild-type BM cells were transplanted into
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Bmi1-deficient recipient mice. These data indicate that Bmi1 is necessary to organize the fully functional BM microenvironment for B lymphopoiesis. We next analyzed cell-autonomous properties of Fit3^+IL7Rα^-c-Kit^+Sca-1^+Lineage^- (FIt3^+IL7Rα^-KSL) multipotent progenitors (MPPs) in vitro. Bmi1^<-/-> Ink4a-Arf^</-> MPPs revealed to be hypersensitive to the IL-7 signal and exhibited drastic proliferation compared with the wild-type and Ink4a-Arf^</-> MPPs. The frequency of B cell-colony-forming cells was also markedly increased in Bmi1^<-/-> Ink4a-Arf^</-> MPPs. By contrast, thymic reconstitutions of irradiated recipient mice were significantly impaired when Bmi1^<-/-> Ink4a-Arf^</-> BM cells were transplanted. To understand the molecular mechanisms responsible for dysregulated lineage commitment of HSCs/MPPs in Bmi1-deficient mice, we compared the gene expression profiles between Bmi1^<-/-> Ink4a-Arf^</-> and Ink4a-Arf^</-> IL7Rα^-c-Kit^+Sca-1^+Lineage^- (IL7RaKSL) HSC/MPPs, and identified that B cell-specific master transcription factor genes Ebf1 and Pax5 and their downstream target genes were prematurely derepressed in Bmi1^<-/-> Ink4a-Arf^</-> HSC/MPPs. Our data suggest that Bmi1 plays an essential role in the regulation of HSC fate decision to lymphoid as well as of B versus T lymphoid lineage choice through regulation of B cell-specific master transcription factor gene expression. Taken together, Bmi1 regulates self-renewal and lineage commitment of HSCs in both cell-autonomous and non-autonomous manners. Less
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Research Products
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