Active and passive DNA demethylation in T cells

2020 Fiscal Year Final Research Report

• 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
• 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.

Free Research Field

T細胞を中心とした免疫学とエピジェネティクスおよびその融合分野

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。