Control of Foxp3 stability through modulation of TET activity
| Autor: | Pandurangan Vijayanand, Sara Trifari, Ageliki Tsagaratou, William A. Pastor, Harri Lähdesmäki, Yun Huang, Anjana Rao, Jorge A. Zepeda-Martínez, Chan-Wang J. Lio, Xiaojing Yue, Tarmo Äijö, Xiang Li |
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| Přispěvatelé: | La Jolla Institute for Allergy and Immunology, Department of Computer Science, Aalto-yliopisto, Aalto University |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Cellular differentiation Immunology chemical and pharmacologic phenomena Ascorbic Acid Biology T-Lymphocytes Regulatory Article Dioxygenases 03 medical and health sciences Cytosine Mice 0302 clinical medicine Proto-Oncogene Proteins Immunology and Allergy Animals Humans Transcription factor Research Articles ta113 Cell growth Protein Stability HEK 293 cells fungi FOXP3 food and beverages hemic and immune systems Cell Differentiation Forkhead Transcription Factors DNA Methylation Ascorbic acid Molecular biology 3. Good health DNA-Binding Proteins 030104 developmental biology DNA demethylation HEK293 Cells DNA methylation 5-Methylcytosine 030215 immunology |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 0022-1007 |
| Popis: | TET2 and TET3 redundantly regulate Foxp3 stability, and their activity can be modulated by vitamin C. 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. |
| Databáze: | OpenAIRE |
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