| Project/Area Number |
17K16180
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Hematology
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| Research Institution | Chiba University |
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Principal Investigator |
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| Research Collaborator |
IWAMA atsushi
OSHIMA motohiko
SHINODA daisuke
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | ポリコーム / Pcgf1 / 骨髄球分化 / JAK2 / ポリコーム群複合体 / PRC1.1 / エピジェネティクス / H2AK119ub1 / 造血幹・前駆細胞 / Cebpa / JAK2V617F / ポリコーム群遺伝子 / 腫瘍 |
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| Outline of Final Research Achievements |
Polycomb repressive complex (PRC) 1 negatively regulates transcription of target genes by mono-ubiquitylation of histone H2A at lysin 119. Pcgf1 is one of the non-canonical PRC1 components. We showed that Pcgf1 negatively regulated myeloid differentiation and proliferation by repressing the gene expression of Cebpa which is known as a critical regulator of myeloid development. It was reported that Pcgf4/Bmi1-containing canonical PRC1 was implicated in the suppression of B cell differentiation and our results suggest the distinct function of Pcgf1-containing non-canonical PRC1.1 and Bmi1-containing canonical PRC1 in hematopoietic differentiation.
We also examined the role of Pcgf1 in a mouse model of JAK2V617F-induced myelofibrosis.JAK2/Pcgf1 KO mice developed lethal myelofibrosis significantly earlier than the other genotypes, suggesting that insufficiency of non-canonical PRC1 complex accelerates the progression of myelofibrosis.
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| Academic Significance and Societal Importance of the Research Achievements |
造血細胞の制御におけるポリコーム群遺伝子の解析はこれまでCanonical PRC1を中心に行われ、重要な役割を果たすことが明らかにされてきた。一方で、近年、白血病など造血器腫瘍の遺伝子解析の結果から、その発症にnon-canonical PRC1の機能不全の寄与が示唆される造血器腫瘍があることがわかってきた。そのようななか、本研究はこれまで明らかにされていなかったnon-canonical PRC1の構成因子Pcgf1の造血細胞分化における役割を明らかにし、また、骨髄線維症をモデルとして病態の進展に関わることを示した。これは造血腫瘍の発症機序解明や治療モデルの確立に繋がる成果といえる。
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