| Project/Area Number |
16K19206
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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 |
Laboratory medicine
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| Research Institution | Chiba University (2017-2019)
Doshisha University (2016) |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | エピジェネティクス / TET2 / 白血病 / 体細胞変異 / 生化学 / EP4遺伝子 / 次世代シーケンス / 腫瘍検査 / 創薬 |
|---|
| Outline of Final Research Achievements |
Missense mutations in Ten-eleven translocation 2 (TET2) gene are frequently found in leukaemia patients. Although mutations span the entire coding region, they tend to cluster in the C-terminal enzymatic domain and a cysteine-rich (CR) domain of unknown function. Herein, we found the CR domain binds chromatin preferentially at the histone H3 tail by recognising H3 lysine 36 mono- and dimethylation (H3K36me1/2). Importantly, missense mutations in the CR domain perturbed TET2 recruitment to the target locus and its enzymatic activities. Our findings identify a novel H3K36me recognition domain and uncover a critical link between histone modification and DNA hydroxylation in leukaemogenesis.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は白血病で高頻度に体細胞変異の起こるTET2の機能未知ドメインがDNA配列変異を超えた意義(エピジェネティクス変異という)、すなわちヒストン修飾を読む機能を持つことを明らかにした。さらに体細胞変異がヒストン修飾の認識を変えることを示した。これらは学術的に興味深いのみならず、白血病に対する創薬について新しいターゲットを提示したという点で応用面でも重要である。
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