Cited by 355T-cell and B-cell ImmunologyEpigenetics and DNA MethylationGenomics and Chromatin Dynamics

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Control of Foxp3 stability through modulation of TET activity

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Yue, Xiaojing, Trifari, Sara, Äijö, Tarmo, Tsagaratou, Ageliki, Pastor, William A., Zepeda-Martínez, Jorge A., Lio, Chan-Wang J., Li, Xiang, Huang, Yun, Vijayanand, Pandurangan, Lähdesmäki, Harri, Rao, Anjana·2016·Journal of Experimental Medicine

DOI 10.1084/jem.20151438PMC PMC4813667

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Abstract

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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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: Äijö, Tarmo
Tsagaratou, Ageliki
Pastor, William A.
Zepeda-Martínez, Jorge A.
Lio, Chan-Wang J.
Huang, Yun
Vijayanand, Pandurangan
Lähdesmäki, Harri
Rao, Anjana
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
DOI: 10.1084/jem.20151438
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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Control of Foxp3 stability through modulation of TET activity

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