Active and passive DNA demethylation in T cells

• Project/Area Number: 18K07164
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Chiba University
• Principal Investigator: Onodera Atsushi 千葉大学, 大学院医学研究院, 准教授 (10586598)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥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)
• 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.

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。

Research Products

• [Int'l Joint Research] La Jolla Institute for Immunology/University of California, San Diego/University of Pennsylvania(米国)
• [Int'l Joint Research] Oxford University/Cambridge University(英国)
• [Int'l Joint Research] La Jolla Institute for Immunology/University of California, San Diego/University of Pennsylvania(米国)
• [Int'l Joint Research] Oxford University/Cambridge University(英国)
• [Int'l Joint Research] La Jolla Institute for Immunology (LJI)/UCSD(米国)
• [Journal Article] The Cxxc1 subunit of the Trithorax complex directs epigenetic licensing of CD4+ T cell differentiation (2021)
  • Author(s): Kiuchi Masahiro、Onodera Atsushi、Kokubo Kota、Ichikawa Tomomi、Morimoto Yuki、Kawakami Eiryo、Takayama Naoya、Eto Koji、Koseki Haruhiko、Hirahara Kiyoshi、Nakayama Toshinori
  • Journal Title: Journal of Experimental Medicine Volume: 218 Issue: 4 Pages: 3-8
  • DOI: 10.1084/jem.20201690
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Essential Role for CD30-Transglutaminase 2 Axis in Memory Th1 and Th17 Cell Generation (2020)
  • Author(s): Suzuki Akane S.、Yagi Ryoji、Kimura Motoko Y.、Iwamura Chiaki、Shinoda Kenta、Onodera Atsushi、Hirahara Kiyoshi、Tumes Damon J.、Koyama-Nasu Ryo、Iismaa Siiri E.、Graham Robert M.、Motohashi Shinichiro、Nakayama Toshinori
  • Journal Title: Frontiers in Immunology Volume: 11 Pages: 1536-1536
  • DOI: 10.3389/fimmu.2020.01536
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ezh2 controls development of natural killer T cells, which cause spontaneous asthma-like pathology (2019)
  • 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.
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 0091-6749(19) Issue: 2 Pages: 30340-9
  • DOI: 10.1016/j.jaci.2019.02.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion (2019)
  • 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.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 25 Pages: 12410-12415
  • DOI: 10.1073/pnas.1905675116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD103hi Treg cells constrain lung fibrosis induced by CD103lo tissue-resident pathogenic CD4 T cells (2019)
  • 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.
  • Journal Title: Nature Immunology Volume: 20 Issue: 11 Pages: 1469-1480
  • DOI: 10.1038/s41590-019-0494-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] エフェクター、メモリーTh2細胞の誘導と維持のエピジェネティクス (2019)
  • Author(s): 小久保幸太、小野寺淳、中山俊憲
  • Journal Title: 臨床免疫／アレルギー科 Volume: 72(2) Pages: 117-122
• [Journal Article] ACC1 determines memory potential of individual CD4+ T cells by regulating de novo fatty acid biosynthesis (2019)
  • 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
  • Journal Title: Nature Metabolism Volume: 1(2) Issue: 2 Pages: 261-275
  • DOI: 10.1038/s42255-018-0025-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Epigenetic and Transcriptional Regulation in the Induction, Maintenance, Heterogeneity, and Recall-Response of Effector and Memory Th2 Cells (2018)
  • Author(s): Onodera A, Kokubo K, Nakayama T
  • Journal Title: Front Immunol. Volume: 9 Pages: 2929-2929
  • DOI: 10.3389/fimmu.2018.02929
  • Peer Reviewed / Open Access
• [Journal Article] Role of leukotriene B4 12-hydroxydehydrogenase in α-galactosylceramide-pulsed dendritic cell therapy for non-small cell lung cancer (2018)
  • Author(s): Tanaka K, Kanesaka Y, Takami M, Suzuki A, Hosokawa H, Onodera A, Kamata T, Nagato K, Nakayama T, Yoshino I, Motohashi S
  • Journal Title: Biochem Biophys Res Commun. Volume: 506(1) Issue: 1 Pages: 27-32
  • DOI: 10.1016/j.bbrc.2018.10.048
  • Peer Reviewed
• [Journal Article] DUSP10 constrains innate IL-33-mediated cytokine production in ST2hi memory-type pathogenic Th2 cells (2018)
  • 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.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 4231-4231
  • DOI: 10.1038/s41467-018-06468-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CXCR6+ST2+ memory T helper 2 cells induced the expression of major basic protein in eosinophils to reduce the fecundity of helminth (2018)
  • Author(s): Obata-Ninomiya, K., Ishiwata, K., Nakano, H., Endo, Y., Ichikawa, T., Onodera, A., Hirahara, K., Okamoto, Y., Kanuka, H., Nakayama, T.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 42
  • DOI: 10.1073/pnas.1714731115
  • Peer Reviewed / Open Access
• [Journal Article] Amphiregulin-Producing Pathogenic Memory T Helper 2 Cells Instruct Eosinophils to Secrete Osteopontin and Facilitate Airway Fibrosis (2018)
  • 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.
  • Journal Title: Immunity Volume: 49 Issue: 1 Pages: 134-150
  • DOI: 10.1016/j.immuni.2018.04.023
  • Peer Reviewed
• [Presentation] アレルギー炎症に伴う線維化に対する新規治療法開発 (2020)
  • Author(s): 平原潔、小野寺淳、飯沼智久、間藤尚子
  • Organizer: 難治性疾患実用化研究事業 免疫アレルギー疾患実用化研究事業 2019年度合同成果報告会
• [Book] 免疫生物学原書第9版 (2019)
  • Author(s): 小野寺淳、中山俊憲（第９章担当）、笹月健彦/吉開泰信（監訳）
  • Total Pages: 910
  • Publisher: 南江堂
  • ISBN: 9784524251155
• [Remarks] 千葉大学大学院医学研究院免疫発生学
  • URL: https://www.m.chiba-u.ac.jp/class/meneki/latest_research/index.html
• [Remarks] 千葉大学大学院医学研究院免疫発生学
  • URL: https://www.m.chiba-u.ac.jp/class/meneki/