Active and passive DNA demethylation in T cells
Project/Area Number |
18K07164
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 49070:Immunology-related
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Research Institution | Chiba University |
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) |
2018-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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Keywords | 免疫記憶 / 発生・分化 / エピジェネティクス / アレルギー・ぜんそく / 発現制御 |
Outline of Final Research Achievements |
DNA demethylation can occur through “passive”, replication-dependent dilution of 5mC and 5hmC as cells divide, which is mediated by TET. A distinct, replication-independent “active” mechanism of DNA demethylation involves excision of 5fC and 5caC by the DNA repair enzyme TDG, followed by base excision repair. In summary, TET enzymes regulate differentiation and DNA demethylation primarily through passive dilution of oxidized mCs in proliferating T-cells. However, active, replication-independent DNA demethylation mediated by TDG does not appear to be essential for immune cell activation or differentiation. We also successfully quantified the occurrence of concordant demethylation within and near enhancer regions in T-cells. Based on the present study, we will further investigate a link between inflammation and impaired DNA methylation and address the therapeutic application and molecular mechanisms that underlie the inflammatory diseases.
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Academic Significance and Societal Importance of the Research Achievements |
研究成果の学術的意義や社会的意義:本研究では、総説等で併記されている、DNAの能動的及び受動的脱メチル化機構の使い分けについて、複数のマウスモデルを用いて検討した。その結果、それら二つが等価ではなく、免疫系の細胞では大部分が後者の受動的な機構に依存していることが明らかとなった。これは基礎生物学上非常に重要な知見である。また、最適化したDNAメチル化の新規検出方法は、今後DNAメチル化異常と炎症性疾患との関連、あるいは腫瘍性疾患の新規診断方法を研究する上で有用なツールとなり、将来的に大きな社会的意義をもたらすと考えている。
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Report
(4 results)
Research Products
(21 results)
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[Journal Article] Ezh2 controls development of natural killer T cells, which cause spontaneous asthma-like pathology2019
Author(s)
Tumes, D., Hirahara, K., Papadopoulos, M., Shinoda, K., Onodera, A., Kumagai, J., Yip, KH., Pant, H., Kokubo, K., Masahiro, K., Aoki, A., Obata-Ninomiya, K., Yokoyoda, K., Endo, Y., Kimura, MY., Nakayama, T.
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Journal Title
Journal of Allergy and Clinical Immunology
Volume: 0091-6749(19)
Issue: 2
Pages: 30340-9
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion2019
Author(s)
Seo H, Chen J, Gonzalez-Avalos E, Samaniego-Castruita D, Das A, Wang YH, Lopez-Moyado IF, Georges RO, Zhang W, Onodera A, Wu CJ, Lu LF, Hogan PG, Bhandoola A, Rao A.
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Journal Title
Proceedings of the National Academy of Sciences
Volume: 116
Issue: 25
Pages: 12410-12415
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] CD103hi Treg cells constrain lung fibrosis induced by CD103lo tissue-resident pathogenic CD4 T cells2019
Author(s)
Ichikawa, T.*, Hirahara, K.*, Kokubo, K.*, Kiuchi, M., Aoki, A., Morimoto, Y., Kumagai, J., Onodera, A., Mato, N., Tumes, D., Goto, Y., Hagiwara, K., Inagaki, Y., Sparwasser, T., Tobe, K., and Nakayama, T.
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Journal Title
Nature Immunology
Volume: 20
Issue: 11
Pages: 1469-1480
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] ACC1 determines memory potential of individual CD4+ T cells by regulating de novo fatty acid biosynthesis2019
Author(s)
Yusuke Endo, Atsushi Onodera, Kazushige Obata-Ninomiya, Ryo Koyama-Nasu, Hikari K. Asou, Toshihiro Ito, Takeshi Yamamoto, Toshio Kanno, Takahiro Nakajima, Kenji Ishiwata, Hirotaka Kanuka, Damon J. Tumes, Toshinori Nakayama
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Journal Title
Nature Metabolism
Volume: 1(2)
Issue: 2
Pages: 261-275
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Role of leukotriene B4 12-hydroxydehydrogenase in α-galactosylceramide-pulsed dendritic cell therapy for non-small cell lung cancer2018
Author(s)
Tanaka K, Kanesaka Y, Takami M, Suzuki A, Hosokawa H, Onodera A, Kamata T, Nagato K, Nakayama T, Yoshino I, Motohashi S
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Journal Title
Biochem Biophys Res Commun.
Volume: 506(1)
Issue: 1
Pages: 27-32
DOI
Related Report
Peer Reviewed
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[Journal Article] DUSP10 constrains innate IL-33-mediated cytokine production in ST2hi memory-type pathogenic Th2 cells2018
Author(s)
Yamamoto, T., Endo, Y., Onodera, A., Hirahara, K., Asou, H., Nakajima, T., Kanno, T., Ouchi, Y., Uematsu, S., Nishimasu, H., Nureki, O., Tumes, D. J., Shimojo, N., and Nakayama, T.
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Journal Title
Nature Communications
Volume: 9
Issue: 1
Pages: 4231-4231
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] CXCR6+ST2+ memory T helper 2 cells induced the expression of major basic protein in eosinophils to reduce the fecundity of helminth2018
Author(s)
Obata-Ninomiya, K., Ishiwata, K., Nakano, H., Endo, Y., Ichikawa, T., Onodera, A., Hirahara, K., Okamoto, Y., Kanuka, H., Nakayama, T.
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Journal Title
Proceedings of the National Academy of Sciences
Volume: 115
Issue: 42
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Amphiregulin-Producing Pathogenic Memory T Helper 2 Cells Instruct Eosinophils to Secrete Osteopontin and Facilitate Airway Fibrosis2018
Author(s)
Morimoto, Y., Hirahara, K., Kiuchi, M., Wada, T., Ichikawa, T., Kanno, T., Okano, M., Kokubo, K., Onodera, A., Sakurai, D., Okamoto, Y., Nakayama, T.
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Journal Title
Immunity
Volume: 49
Issue: 1
Pages: 134-150
DOI
Related Report
Peer Reviewed
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