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Control of Foxp3 stability through modulation of TET activity
Open accessAbstract
Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine and other oxidized methylcytosines, intermediates in DNA demethylation. In this study, we examine the role of TET proteins in regulating Foxp3, a transcription factor essential for the development and function of regulatory T cells (T reg cells), a distinct lineage of CD4+ T cells that prevent autoimmunity and maintain immune homeostasis. We show that during T reg cell development in the thymus, TET proteins mediate the loss of 5mC in T reg cell–specific hypomethylated regions, including CNS1 and CNS2, intronic cis-regulatory elements in the Foxp3 locus. Similar to CNS2-deficient T reg cells, the stability of Foxp3 expression is markedly compromised in T reg cells from Tet2/Tet3 double-deficient mice. Vitamin C potentiates TET activity and acts through Tet2/Tet3 to increase the stability of Foxp3 expression in TGF-β–induced T reg cells. Our data suggest that targeting TET enzymes with small molecule activators such as vitamin C might increase induced T reg cell efficacy.
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“The catalytic activity of all three TET family members (TET1, 2 and 3) are induced by vitC,13, 26”
From Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia (2018) · cites this paper as [26]
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Metadata
- Authors
- Yue, X., Trifari, S., Äijö, T., Tsagaratou, A., Pastor, W. A., Zepeda-Martínez, J. A., Lio, C.-W. J., Li, X., Huang, Y., Vijayanand, P., Lähdesmäki, H., & Rao, A.
- Affiliations
- La Jolla Institute for Immunology (US)
- Aalto University (FI)
- Corresponding author
- Rao, Anjana
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2016-02-22
- Volume
- 213
- Issue
- 3
- Pages
- 377-397
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC4813667
- OpenAlex
- W2287054877
- Cited by
- 355
- References
- 60
- Citations by year
- 2026: 34 · 2025: 23 · 2024: 29 · 2023: 33 · 2022: 34 · 2021: 41 · 2020: 39 · 2019: 43 · 2018: 27 · 2017: 38 · 2016: 12
- FWCI
- 24.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Aaltodoc (Aalto University) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health (AI44432, CA151535, HL114093)
- Leukemia and Lymphoma Society (LLS TRP 6464-15)
- Academy of Finland
- Cancer Research Institute
- National Science Foundation
- California Institute for Regenerative Medicine, University of California, San Diego (TG2-01154)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- Foxp3 stability, TET enzymes, TET2, TET3, regulatory T cells, DNA demethylation, 5-hydroxymethylcytosine, 5-methylcytosine, vitamin C, transcriptional regulation, small molecule activators
- MeSH terms
- Animals, Ascorbic Acid, Cell Differentiation, Cytosine, DNA-Binding Proteins, Humans, Male, Proto-Oncogene Proteins, DNA Methylation, 5-Methylcytosine, Dioxygenases, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Protein Stability, HEK293 Cells
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