| Project/Area Number |
17K08643
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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 |
General medical chemistry
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| Research Institution | Takasaki University of Health and Welfare |
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Principal Investigator |
Ohmori Shin'ya 高崎健康福祉大学, 薬学部, 講師 (10509194)
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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 |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 転写因子 / GATA2 / PU.1 / C/EBPa / マスト細胞 / 形質転換 / 転写制御 / ヒストン修飾 / Cebpa / 血球分化 / GATA1 / 分化・発生 / 遺伝子発現制御 |
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| Outline of Final Research Achievements |
In this study, we examined molculer basis of of Cebpa transcriptional repression by mast transcription factors.The simultaneous KD of PU.1 and GATA2 in mast cells resulted in a significant reduction of the Cebpa expression compared to that in the cells transfected with GATA2 siRNA. Furthermore, deletion of GATA2 resulted in increased PU.1 binding in the downstream of Cebpa gene. We then examined the changes in histone modifications after deletion of GATA2. The GATA2 deletion increased the acetylation of histone H3 at the gene body and downstream of Cebpa gene. CBP functions as a coactivator for PU.1. However, inhibition of acetylation with P300 inhibitor (A-485) did not increase the binding of PU.1 in the downstream of Cebpa gene. These results suggest that in the up-regulation of Cebpa by GATA2 deletion in mast cells, PU. 1 may be involved in the rapid up-regulation of Cebpa rather than trigger the onset of expression.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究課題では、マスト細胞で認められたGATA2欠失によるCebpaの脱抑制機構にPU.1が正の制御因子として働くことを明らかにし、またPU.1は発現開始のトリガーではなく、その後の発現上昇に関与していることを見出した。これまでにPU.1は骨髄球の分化過程においてCebpaの正の制御因子として報告されているが、その詳しい制御メカニズムは不明である。また好塩基球ではGATA2、PU.1、C/EBPaが全て発現しており、マスト細胞の近縁と考えられているにもかかわらずその制御機構は全く異なっている可能性が考えられる。本研究課題で得られた成果は、これらの分子基盤の解明の足がかりとなることが期待される。
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