title: Control of Foxp3 stability through modulation of TET activity.
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.
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yue
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Sara
authors.initials: S
authors.lastname: Trifari
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037 Department of Computer Science, Aalto University School of Science, 00076 Aalto, Finland.
authors.forename: Tarmo
authors.initials: T
authors.lastname: Äijö
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Ageliki
authors.initials: A
authors.lastname: Tsagaratou
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: William A
authors.initials: WA
authors.lastname: Pastor
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Zepeda-Martínez
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Chan-Wang J
authors.initials: CW
authors.lastname: Lio
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037 Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Pandurangan
authors.initials: P
authors.lastname: Vijayanand
authors.affiliation: Department of Computer Science, Aalto University School of Science, 00076 Aalto, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Lähdesmäki
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037 Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037 Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093 arao@liai.org.
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D049308:Dioxygenases; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D055550:Protein Stability / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011518:Proto-Oncogene Proteins; D044503:5-Methylcytosine; D003596:Cytosine; D049308:Dioxygenases; C551914:Tet2 protein, mouse; C551915:Tet3 protein, mouse; D001205:Ascorbic Acid