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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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“support Treg induction include vitamin D, retinoic acid, vitamin C, and inhibition of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI-3 kinase) (21) (22).”
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BackgroundSelf-citationVitamin C deficiency reveals developmental differences between neonatal and adult hematopoiesis
Phadke, I., Pouzolles, M., Machado, A., Moraly, J., González‐Menéndez, P., Zimmermann, V. S., Kinet, S., Levine, M., Violet, P.-C., & Taylor, N. N. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.898827 · Cited by 16
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Yong, C. S. M., Moussa, D. A., Cretenet, G., Kinet, S., Dardalhon, V., & Taylor, N. N. (2017) · FEBS Letters · doi:10.1002/1873-3468.12849 · Cited by 16
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Micro but mighty—Micronutrients in the epigenetic regulation of adaptive immune responses*
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Self-citationRegulatory T Cell-Based Adoptive Cell Therapy in Autoimmunity
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“…TGF-β [141,142], the use of ascorbate (vitamin C) that could facilitate de novo hypomethylation of Foxp3 CNS2 in iTregs through Tet activation [143,144], the use of epigenetic regulators (e.g., inhibition of HDAC6 [145–147]), and transgenic overexpression of the transcription factors FOXP3,…”
L’hématopoïèse clonale : un concept émergent à la croisée des spécialités
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“While Dnmt1 promotes methylation, Tet1/2 are required for demethylation and the maintenance of Foxp3 expression ( 20 – 22 ).”
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Inflammatory and Immune Disorders Associated with Myelodysplastic Syndromes
Jachiet, V., Fenaux, P., Sevoyan, A., Hakobyan, Y. K., Adès, L., Fain, O., MEKINIAN, A., & GFM, O. B. O. T. M. A. (2021) · Hemato · doi:10.3390/hemato2020019 · Cited by 16
“- The inactivating mutations of TET2 and DNMT3A could favor a pro-inflammatory state of monocytic and macrophagic cells [44,45] and/or modify the activity of CD8 T lymphocytes and the polarization of the CD4 T lymphocytes, since TET2 regulates the methylation of the promoter regions of FOXP3 gene [46] and genes of tra…”
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Xu, T., Pereira, R. M., & Martínez, G. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2100633 · Cited by 14
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Kalinka, A., Starczak, M., Gackowski, D., Stępień, E., & Achrem, M. (2023) · Journal of Experimental Botany · doi:10.1093/jxb/erad102 · Cited by 13
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Empowering γδ T‐cell functionality with vitamin C
Kabelitz, D., Cierna, L., Juraske, C., Zarobkiewicz, M. K., Schamel, W. W. A., & Peters, C. (2024) · European Journal of Immunology · doi:10.1002/eji.202451028 · Cited by 12
“Through activation of TET enzymes, VitC induces hypomethylation in specific CpG sites of FoxP3 thereby leading to increased stability of FoxP3 protein and suppressive function of regulatory T cells (Treg) [40, 41, 42].”
BackgroundEpigenetic regulation of inflammation by CxxC domain‐containing proteins*
Onodera, A., Kiuchi, M., Kokubo, K., & Nakayama, T. (2021) · Immunological Reviews · doi:10.1111/imr.13056 · Cited by 12
TET2 Regulates 5-Hydroxymethylcytosine Signature and CD4+ T-Cell Balance in Allergic Rhinitis
Tan, L., Fu, L., Zheng, L., Fan, W., Tan, H., Tao, Z., & Xu, Y. (2022) · Allergy Asthma and Immunology Research · doi:10.4168/aair.2022.14.2.254 · Cited by 11
Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys
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“This is true of the FOXP3 locus and, importantly, the CD4 locus (33, 34).”
Jin, M., Ji, J., Chen, X., Zhou, Y. Y., Wang, D., & Liu, A.-X. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1066599 · Cited by 11
Regulatory T Cells for Control of Autoimmunity
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Concomitant loss of TET2 and TET3 results in T cell expansion and genomic instability in mice
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“Due to the accelerated death it was not possible to dissectwhetherlossofTETproteinsmightimpactCD4Tcellexpansion 18,22 .”
InfluentialSelf-citationDNA (Hydroxy)Methylation in T Helper Lymphocytes
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“Other subsets include TH17 cells (characterized by the expression of IL-17 and the transcription factor RORC) and regulatory Treg cells, characterized by FOXP3 expression and immune suppressive functions [1, 2].”
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Tsagaratou, A. (2018) · Molecular Immunology · doi:10.1016/j.molimm.2018.08.020 · Cited by 10
Self-citationDevelopment and Functional Modulation of Regulatory T Cells by Transcription Factors and Epigenetics
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TET Proteins in the Spotlight: Emerging Concepts of Epigenetic Regulation in T Cell Biology
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“Mechanistically, this was attributed to enhanced TET enzymatic activity and DNA demethylation of the CNS2 locus of FOXP3, maintaining stable FOXP3 expression (36).”
BackgroundInfluentialSelf-citationThymic origins of autoimmunity—lessons from inborn errors of immunity
Bacchetta, R., & Weinberg, K. I. (2021) · Seminars in Immunopathology · doi:10.1007/s00281-020-00835-8 · Cited by 10
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“methylcytosine dioxygenase that catalyzes the demethylation of cytosines) to TSDR and maintained the demethylated CpG sites in the Foxp3 locus (62, 63).”
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Applications of CRISPR Epigenome Editors in Tumor Immunology and Autoimmunity
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Metabolic adaptation orchestrates tissue context‐dependent behavior in regulatory T cells
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EnvIRONmental Aspects in Myelodysplastic Syndrome
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Stepwise acquisition of unique epigenetic signatures during differentiation of tissue Treg cells
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“Mechanistically, the imprinting of the epigenetic signature occurs through an active process involving enzymes of the Ten-eleventranslocation (Tet) family, which act by iterative oxidation of 5mC to 5hmC, finally resulting in the demethylation of the CpG motif (14, 60, 62).”
BackgroundDNA demethylation fine‐tunes IL‐2 production during thymic regulatory T cell differentiation
Teghanemt, A., Misel‐Wuchter, K., Heath, J., Thurman, A. L., Pulipati, P., Dixit, G., Geesala, R., Meyerholz, D. K., Maretzky, T., Pezzulo, A. A., et al. (2023) · EMBO Reports · doi:10.15252/embr.202255543 · Cited by 9
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TET2 regulates immune tolerance in chronically activated mast cells
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“TET2 also plays a major role in the lymphoid compartment, in maintaining regulatory T cells by the stabilization of FoxP3 [30], modulating B germinal center reaction [31], and, as found by our group, regulating NK lymphocyte cytotoxicity [32].”
BackgroundDeciphering the TET3 interactome in primary thymic developing T cells
Theofilatos, D., Ho, T., Waitt, G. M., Äijö, T., Schiapparelli, L., Soderblom, E. J., & Tsagaratou, A. (2024) · iScience · doi:10.1016/j.isci.2024.109782 · Cited by 8
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“APC and GSK3b are well studied negative regulators of b-catenin, and recent studies showed that Foxp3 inhibits IL-17A expression(11) and TET2 stimulates Foxp3 expression.(12) In addition, previous studies showed that TET2(13) and Foxp3(14) are targets of miR-125a, although not in GCTB.”
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“suggested that Vitamin C could promote iTreg development in mouse by promoting CNS2 demethylation by the TET enzymes in clinical setups (100, 101), especially in hypoxic conditions (102).”
BackgroundThe roles of epigenetic regulation in graft-versus-host disease
Wang, Y., Liu, Q., Deng, L., Ma, X., Gong, Y., Wang, Y., & Zhou, F. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116652 · Cited by 6
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Unraveling the Epigenetic Regulation of Regulatory T Cells in Cancer Immunity
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“Likewise, active DNA demethylation via Ten-Eleven Translocation (Tet) enzymes stabilizes Foxp3 expression through CNS2, controlling multiple gene expressions [32,35].”
InfluentialSuzuki, K., Arteaga-Vazquez, L. J., Reveles, B. V., Hernández-Espinosa, L., López-Moyado, I. F., Onodera, A., Samaniego‐Castruita, D., Ay, F., Lara-Custodio, A., Hogan, P. G., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1684023 · Cited by 6
Self-citationThe TET-TDG axis in T cells and biological processes
Suzuki, K., Rao, A., & Onodera, A. (2025) · International Immunology · doi:10.1093/intimm/dxaf006 · Cited by 5
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“This corresponds to lower levels of demethylation of the TSDR in iTreg [23–25] and can be improved by implementation of specific protocols that promote DNA demethylation, such as addition of vitamin C [26] or retinoic acid [27] or withdrawal of CD28 signaling during Treg induction [28].”
BackgroundT-regulatory cells require Sin3a for stable expression of Foxp3
Christensen, L. M., Akimova, T., Wang, L., Han, R., Samanta, A., Giorgio, E. D., & Hancock, W. W. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1444937 · Cited by 4
Unveiling vitamin C: A new hope in the treatment of diffuse large B‑cell lymphoma (Review)
Ren, C., Li, Y., Li, M., & Wang, Y. (2025) · International Journal of Oncology · doi:10.3892/ijo.2025.5746 · Cited by 4
“Vitamin C can enhance the activity of TET enzymes, suggesting that targeting TET enzymes with vitamin C may improve the efficacy of Treg cell induction (53).”
Immune Cell Development and Epigenetics
Sekiya, T. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-809912-4.00002-7 · Cited by 4
Ex-TFRs: A Missing Piece of the SLE Puzzle?
Wei, X., Zhang, J., & Zhou, X. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.662305 · Cited by 4
“Gradual demethylation of CNS2 occurs during tTreg development (67, 68); this process is not passively cell cycle dependent but is mediated by Tet-dependent oxidation, which is primarily mediated by Tet2 and Tet3 (69).”
BackgroundLi, J.-J., Zhang, X., Zheng, L., & Liu, Y. (2017) · Neoplasma · doi:10.4149/neo_2017_514 · Cited by 4
“It’s suggested that frequent FOXP3 gene mutations and deletions, which may include nuclear localization signals surrounding the FKH domain of FOXP3, post-translational modifications, splice variations and the methylation of FOXP3 promoter may result in cytoplasmic localization of FOXP3 protein in breast cancer cells […”
BackgroundColson, T. R., Cameron, J. J., Muendlein, H. I., Nolan, M.-A., Leiriao, J. L., Kim, J. H., Poltorak, A., & Li, X. J. (2025) · JCI Insight · doi:10.1172/jci.insight.185581 · Cited by 7
Self-citationÄijö, T., Gioulbasani, M., Valenzuela, J. E., & Tsagaratou, A. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1638500 · Cited by 3
“TET proteins are implicated in Treg stability (25, 41 – 44) and Treg function (26, 45, 46).”
Self-citationLi, L., Huang, H., Wang, H., Pan, Y., Tao, H., Zhang, S., Karmaus, P. W. F., Fessler, M. B., Sleasman, J. W., & Zhong, X. (2026) · eLife · doi:10.7554/elife.105212.3 · Cited by 4
TET proteins regulate Drosha expression and impact microRNAs in iNKT cells
Gioulbasani, M., Äijö, T., Valenzuela, J. E., Bettes, J. B., & Tsagaratou, A. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1440044 · Cited by 3
“Specifically, TET2 and TET3 are fundamental for the stability of the transcription factor (TF) FOXP3 and thus the functionality and stability of regulatory T cells (Tregs) (12).”
BackgroundSelf-citationZhao, M., Peng, C., Li, L., Chen, L., & Zhang, H. (2020) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13388 · Cited by 3
The Role of TET Proteins in B Cell Biology
Tanaka, S., Ise, W., Baba, Y., & Kurosaki, T. (2020) · Journal of Immunological Sciences · doi:10.29245/2578-3009/2021/1.1202 · Cited by 3
Satb1 enforces CD4+ effector T cell lineage stability by repressing Foxp3 via DNA methylation
Seo, W., Zou, C., Nair, K., Koseki, H., Kohwi-shigematsu, T., Nishikawa, H., & Taniuchi, I. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.154026 · Cited by 2
Abbas, M. A. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27135778 · Cited by 2
“This leads to a measurable recovery of suppressive function, although the degree of reversibility appears to depend on the proliferative and inflammatory history of the cells [107].”
Yahaya, A., Hashim, S., & Yazit, S. (2010) · Cited by 2
Vitamin C in Health and Disease: From Redox Biology to Clinical Medicine
Li, Y. R. (2024) · Advances in biochemistry in health and disease · doi:10.1007/978-3-031-55474-2_16 · Cited by 2
Understanding Myelodysplasia and Inflammation Through the Lense of VEXAS Syndrome: A Review
Wolff, L., Caratsch, L., Zhao, L., Blum, S., & Comte, D. (2024) · Cells · doi:10.3390/cells13221890 · Cited by 2
Autoimmune disease and epigenetics
Blossom, S. J. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-823928-5.00009-8 · Cited by 2
Can polyamine metabolism in T helper cell lineage commitment be a new target in allergy research?
Huang, M., & Rodríguez‐Coira, J. (2022) · Allergy · doi:10.1111/all.15265 · Cited by 2
TET enzymes augment AID expression via 5hmC modifications at the Aicda superenhancerPreprint
Lio, C. J., Shukla, V., Samaniego‐Castruita, D., González‐Avalos, E., Chakraborty, A., Yue, X., Schatz, D. G., Ay, F., & Rao, A. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/438531 · Cited by 2
“Although WGBS cannot distinguish 5mC and 5hmC (27), 5hmC is typically a small fraction (1-10%) of 5mC (28), thus we refer to the WGBS signal as “DNA methylation” here.”
BackgroundSelf-citationIL-2–induced Stat3 Signaling is Critical for Effector Treg Cell ProgrammingPreprint
Dean, E. C., Ditoro, D. F., Pham, D., Gao, M., Zindl, C. L., Frey, B. F., Harbour, S. N., Figge, D. A., Miller, A. T., Glassman, C. R., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.26.559434 · Cited by 2
Mukherjee, K., & Bhattacharyya, S. N. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1708031 · Cited by 1
“Methods that inhibit DNA methyltransferases (DNMTs) and promote the activity of ten-eleven translocation (TET) enzymes can increase FOXP3 expression and enhance Treg stability (140).”
Clinical immunology in chromatinopathies: a scoping review
Jans, D., Al, B., Bouman, A., Geelen, J. M., Kleefstra, T., & Placek, K. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1773284 · Cited by 1
Control of naive T cell reactivity and peripheral tolerance by ascorbate and TET activity
Hao, X., Bai, L., Li, J., Xu, B., Janke, L. J., Palacios, G., Guy, C. S., Crawford, J. C., Fan, Y., Rosikiewicz, W., et al. (2026) · Science Advances · doi:10.1126/sciadv.aeh1439 · Cited by 1
Precision Immunoregulation in transplantation: The rise of engineered Treg therapies
Azhar, A., Mir, T. A., Khan, M. A., Alzhrani, A., Salma, J., Kazmi, S., Assiri, A. M., Broering, D. C., & Yaqinuddin, A. (2026) · Molecular Biology Reports · doi:10.1007/s11033-026-12310-y · Cited by 1
“TSDRs are demethylated to preserve FOXP3 expression, primarily through the activity of TET2 and TET3, particularly in peripheral Tregs [91].”
Alvarez-Salazar, E. K., Reyes-Barrientos, J. E., Cortés-Hernández, A., Castellanos, A. S.-M., Arteaga-Cruz, S., Cervera, A., Martínez-Iturbe, I., Sánchez-Hernández, B. E., Gamboa‐Domínguez, A., & Soldevila, G. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1827886 · Cited by 1
“This is consistent with previous studies showing that vitamin C promotes TSDR demethylation by increasing TET enzymatic activity, as re fl ected by enhanced conversion of 5-methylcytosine to 5-hydroxymethylcytosine, without altering TET or DNMT transcription (21, 26, 27).”
Rag1-based time-stamp tracing of T-cell developmental origins
Jiang, M., Li, Y., Zong, X., Hao, X., Guy, C., Rosikiewicz, W., He, M., Bai, L., Huang, W., Choudhary, V., et al. (2026) · The Journal of Immunology · doi:10.1093/jimmun/vkag154 · Cited by 1
“38 To determine whether time-stamp tracing can resolve events associated with Treg cell lineage commitment, we examined the phenotypic and molecular maturation of nascent Foxp3 + CD4 SP thymocytes.”
Chen, Y., Shi, Y., & You, J. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02910-2 · Cited by 1
“The enhancement of the catalytic activity of Tet family enzymes using hydrogen sul fi de, 240 vitamin C, 243,244 and ascorbic acid (ASC) 235 has been demonstrated to promote TSDR demethylation and achieve stable Foxp3 expression.”
Vitamin C: Current Concepts in Human Physiology
Carr, A. C., & Natarajan, R. (2018) · MDPI eBooks · doi:10.3390/books978-3-03897-295-2 · Cited by 1
Understanding immune system development: An epigenetic perspective
Madhok, A., deSouza, A., & Galande, S. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-817964-2.00003-4 · Cited by 1
Role of Regulatory T cells in Prognosis, Diagnosis, and Treatment of Kidney Transplant Recipients
Bejugama, K., & Guditi, S. (2023) · Journal of Cellular Immunology · doi:10.33696/immunology.5.181 · Cited by 1
Wilkins, O. M., Johnson, K. C., Houseman, E. A., King, J. E., Marsit, C. J., & Christensen, B. C. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/339069 · Cited by 1
Matias, M. I., Yong, C. S. M., Foroushani, A. B. K., Sezgin, E., Levental, K. R., Talebi, A., Mongellaz, C., Dehair, J., Wong, M., Kinet, S., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.24.256560 · Cited by 1
“…dependent on αKG for the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) (Lio and Rao, 2019; Rose et al., 2011; Tahiliani et al., 2009), are required for Treg stability and immune homeostasis (Nakatsukasa et al., 2019; Yang et al., 2015; Yue et al., 2019; Yue et al., 2016).”
Background
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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