Analysis of the molecular basis of mast cell-specific gene transcription by Gata1/Gata2 and PU.1.
| Project/Area Number |
18K06920
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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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| Review Section |
Basic Section 48040:Medical biochemistry-related
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| Research Institution | Tohoku University (2019-2020)
Takasaki University of Health and Welfare (2018) |
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Principal Investigator |
Ohneda Kinuko 東北大学, 東北メディカル・メガバンク機構, 教授 (50323291)
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| Co-Investigator(Kenkyū-buntansha) |
大森 慎也 高崎健康福祉大学, 薬学部, 講師 (10509194)
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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 |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 転写因子 / 遺伝子発現制御 / マスト細胞 / 高親和性IgE受容体 / 細胞分化 / 遺伝子発現 |
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| Outline of Final Research Achievements |
GATA1/GATA2 and PU.1 are known to function antagonistically during hematopoietic development. However, these factors are co-expressed in mast cells, and activate the expression of the Ms4a2 gene encoding the β chain of the high-affinity IgE receptor (FcεRI). The present study investigated the roles of GATA2 and PU.1 on Ms4a2 gene transcription. Gene ablation experiments revealed that GATA2 and PU.1 almost equally contributed to the Ms4a2 gene expression. A chromatin immunoprecipitation analysis showed that they shared DNA binding to the +10.4 kb region downstream of the Ms4a2 gene, whereas the proximal -0.06 kb region was exclusively bound by GATA2. Furthermore, we showed that the ablation of the +10.4 kb region by genome editing abolished the Ms4a2 gene expression. Collectively, these results suggest that PU.1 plays central roles in the formation of active chromatin structure, whereas GATA2 directly activates the Ms4a2 promoter.
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| Academic Significance and Societal Importance of the Research Achievements |
GATA転写因子とPU.1がお互いの発現を抑制し拮抗的に作用することは、血球細胞の分化過程で重要な分子基盤として知られてきた。本研究では、Ms4a2遺伝子の発現制御機構をモデルとしてGATA2とPU.1の協調的作用を示し、マスト細胞には従来知られていた両者の拮抗的作用とは異なる転写因子ネットワークが存在することを示した。ヒトMs4a2遺伝子のコード領域のバリアントは気管支喘息等のリスクと関連する。今回明らかにした遺伝子発現制御の仕組みがヒトでも保存されていれば、同遺伝子の非コード領域においても、病的バリアントや構造多型がヒト疾患リスクに関与している可能性がある。
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Report
(4 results)
Research Products
(13 results)
