Heterochromatin dysfunction and its related diseases induced by impaired DNA demethylation
| Project/Area Number |
20KK0351
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| Research Category |
Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 49070:Immunology-related
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| Research Institution | Chiba University |
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Principal Investigator |
ONODERA Atsushi 千葉大学, 大学院医学研究院, 准教授 (10586598)
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| Project Period (FY) |
2021 – 2022
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000)
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| Keywords | エピジェネティクス / 発生・分化 / 第三世代シークエンス / 炎症性疾患 / 発現制御 |
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| Outline of Research at the Start |
申請者は今まで一貫してT細胞のepigenetic研究、特にヒストン修飾やDNAシトシンメチル化に着目して、ゲノム上で発現が見られる遺伝子領域（ユークロマチン）を解析してきた。一方、ゲノム上で発現が抑制されている領域（ヘテロクロマチン）は、検出技術の限界もあり解析が難しいが、同領域の転移因子（トランスポゾン）の再活性化が、炎症や細胞癌化に重要との報告が近年相次いでいる。そこで本研究では、基課題で培った実験系を発展させ、ヘテロクロマチンでのシトシンメチル化と転移因子の再活性化の関係性解明に挑戦し、さらには疾患（炎症性亢進および腫瘍化）の関連を明らかにして、疾患制御に進展をもたらしたい。
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| Outline of Final Research Achievements |
We analyzed the association between elevated RNA transposon expression due to heterochromatin dysfunction and the leukemogenesis by using TET-deficient mice as a model. Experimental data were obtained at the La Jolla Institute for Immunology, the main collaborating overseas research institute. Data analysis was supported by University of California, San Diego. As a result of our research, we found a region where heterochromatin was switched to euchromatin by TET deficiency, and RNA transposon expression was induced. The region encodes the Stefin gene cluster, whose human homolog gene expression levels were well-correlated with cancer patients’ prognosis. These findings indicate that heterochromatin dysfunction potentially leads to leukemogenesis through upregulation of RNA transposons.
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| Academic Significance and Societal Importance of the Research Achievements |
ヘテロクロマチン機能不全と疾患発症の関係性を明らかにした報告は少なく、本研究で発表した論文は両者の関係を裏付ける学術的に大きな成果であった。また、ヘテロクロマチンが機能不全を起こす領域にクラスターを形成するStefin遺伝子のヒトにおけるホモログ遺伝子群の高発現は、がん患者の予後に悪影響を与えることが分かった。これらの知見は、Stefin遺伝子群の発現が、がん患者の予後や治療感受性を予測できるバイオマーカーとして使える可能性を示唆し、社会的意義のある研究成果であると言える。
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Report
(3 results)
Research Products
(20 results)
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[Presentation] Unsaturated fatty acids promote pathogenic type 2 adaptive immunity via PPARg-ST2 axis. International Symposium for Future Mucosal Vaccines2023
Author(s)
Yagyu, H., Kiuchi, M., Kokubo, K., Sasaki, A., Onodera, A., Iwamura, C., Kaneko, T., Nakayama T., and Hirahara, K.
Organizer
Safeguards and Innovations against Infectious Diseases
Related Report
Int'l Joint Research
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[Presentation] CD69 regulates anti-tumor CD8T cell responses.2023
Author(s)
Nasu, R., Wang, YS., Endo, Y., Hasegawa, I., Mita, Y., Onodera, A., Motohashi, S., Nakayama T., and Kimura KY.
Organizer
International Symposium for Future Mucosal Vaccines: Safeguards and Innovations against Infectious Diseases
Related Report
Int'l Joint Research
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[Presentation] Connecting TET2 deficiency with inflammation in CMML and anti-tumor responses.2022
Author(s)
Singh, AK., Onodera, A., Lopez-Moyado, IF., Sepulveda, H., Angel, JC., Rao, A.
Organizer
AACR, New Orleans, USA
Related Report
Int'l Joint Research
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