The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells
Open accessAbstract
Epigenetic regulation of lineage-specific genes is important for the differentiation and function of T cells. Ten-eleven translocation (Tet) proteins catalyze 5-methylcytosine (5 mC) conversion to 5-hydroxymethylcytosine (5 hmC) to mediate DNA demethylation. However, the roles of Tet proteins in the immune response are unknown. Here, we characterized the genome-wide distribution of 5 hmC in CD4(+) T cells and found that 5 hmC marks putative regulatory elements in signature genes associated with effector cell differentiation. Moreover, Tet2 protein was recruited to 5 hmC-containing regions, dependent on lineage-specific transcription factors. Deletion of Tet2 in T cells decreased their cytokine expression, associated with reduced p300 recruitment. In vivo, Tet2 plays a critical role in the control of cytokine gene expression in autoimmune disease. Collectively, our findings suggest that Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells.
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TET2 has been shown to act via both 5mC oxidation and catalytic-independent mechanisms, such as recruitment of epigenetic modifiers.
“TET2 has been shown to act via both 5mC oxidation and catalytic-independent mechanisms, such as recruitment of epigenetic modifiers (Ichiyama et al., 2015), (Zhang et al., 2015).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Ichiyama et al., 2015
The Introduction describes TET-mediated oxidation of 5mC, and the Results report reduced p300 recruitment in Tet2-deficient Th1 and Th17 cells (page numbers unavailable in our copy). These findings support a link between Tet2 and an epigenetic modifier, but the paper does not establish that the p300 effect is independent of Tet2’s catalytic activity. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn T helper cells, TET2 mediates demethylation of putative regulatory elements in genes associated with T cell differentiation, regulating the Th1 and Th17 cytokine expression in vitro.
“In T helper cells, TET2 mediates demethylation of putative regulatory elements in genes associated with T cell differentiation, regulating the Th1 and Th17 cytokine expression in vitro (Ichiyama et al., 2015).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Ichiyama et al., 2015
TET2 plays important roles during the inflammatory response in different peripheral immune cells.
“Recent reports have shown that TET2 plays important roles during the inflammatory response in different peripheral immune cells (Ichiyama et al., 2015)(Tsagaratou et al., 2016)(Zhang et al., 2015)(Cull et al., 2017).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Ichiyama et al., 2015
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References 32 · Cited by 327
Research works printed but not linked: 28
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- Authors
- Ichiyama, K., Chen, T., Wang, X., Yan, X., Kim, B.-S., Tanaka, S., Ndiaye-Lobry, D., Deng, Y., Zou, Y., Zheng, P., Tian, Q., Aifantis, I., Wei, L., & Dong, C.
- Affiliations
- Children's National (US)
- Sun Yat-sen University (CN)
- Tsinghua University (CN)
- Institute for Systems Biology (US)
- The University of Texas MD Anderson Cancer Center (US)
- Immunology Frontier Research Center, The University of Osaka (JP)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wei, Lai
- Dong, Chen
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 42
- Issue
- 4
- Pages
- 613-626
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC4956728
- OpenAlex
- W2040151622
- Cited by
- 327
- References
- 32
- Citations by year
- 2026: 18 · 2025: 17 · 2024: 21 · 2023: 26 · 2022: 34 · 2021: 33 · 2020: 41 · 2019: 37 · 2018: 32 · 2017: 32 · 2016: 25 · 2015: 11
- FWCI
- 14.48
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-06-16)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute on Aging (R01AG036690)
- National Cancer Institute (P30CA016672)
- National Institute of Allergy and Infectious Diseases (R01AI106654)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-050772, R01AR050772)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- TET2, DNA demethylation, 5-hydroxymethylcytosine, 5-methylcytosine, CD4+ T cells, cytokine gene expression, epigenetic regulation, P300, effector T cell differentiation, autoimmune disease, lineage-specific transcription factors
- MeSH terms
- T-bet Transcription Factor, Animals, Cell Differentiation, Cytosine, DNA, DNA-Binding Proteins, Gene Expression Regulation, Humans, Mice, Transgenic, Proto-Oncogene Proteins, Cytokines, Genome, Th1 Cells, DNA Methylation, T-Box Domain Proteins, Epigenesis, Genetic, 5-Methylcytosine, Dioxygenases, STAT4 Transcription Factor, E1A-Associated p300 Protein, Mice, Th17 Cells
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