A novel upstream enhancer of FOXP3, sensitive to methylation-induced silencing, exhibits dysregulated methylation in rheumatoid arthritis Treg cells

European Journal of Immunology

Volumn 44, Issue 10, 2014, Pages 2968-2978

  Kennedy, Alan ^a   Schmidt, Emily M ^a   Cribbs, Adam P ^a   Penn, Henry ^b   Amjadi, Parisa ^a   Syed, Khaja ^a   Read, Jordan E ^a   Green, Patricia ^a   Gregory, Bernard ^a   Brennan, Fionula M ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b NORTHWICK PARK HOSPITAL   (United Kingdom)

Author keywords

DNA methylation; Foxp3; Regulatory T cells; Rheumatoid arthritis

Indexed keywords

ADALIMUMAB; DNA METHYLTRANSFERASE 1; DNA METHYLTRANSFERASE 3A; ETANERCEPT; HYDROXYCHLOROQUINE; MESSENGER RNA; METHOTREXATE; PREDNISOLONE; RHEUMATOID FACTOR; RITUXIMAB; SALAZOSULFAPYRIDINE; TRANSCRIPTION FACTOR FOXP3; FORKHEAD TRANSCRIPTION FACTOR; FOXP3 PROTEIN, HUMAN;

ADULT; AGED; ARTICLE; BLOOD; CLINICAL ARTICLE; CONTROLLED STUDY; CPG ISLAND; DNA METHYLATION; HUMAN; MIDDLE AGED; PRIORITY JOURNAL; PROTEIN EXPRESSION; REAL TIME POLYMERASE CHAIN REACTION; REGULATORY T LYMPHOCYTE; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RHEUMATOID ARTHRITIS; X CHROMOSOME INACTIVATION; FEMALE; FLOW CYTOMETRY; GENE EXPRESSION REGULATION; GENETICS; IMMUNOLOGY; MALE;

ADULT; AGED; ARTHRITIS, RHEUMATOID; DNA METHYLATION; FEMALE; FLOW CYTOMETRY; FORKHEAD TRANSCRIPTION FACTORS; GENE EXPRESSION REGULATION; HUMANS; MALE; MIDDLE AGED; REAL-TIME POLYMERASE CHAIN REACTION; T-LYMPHOCYTES, REGULATORY;

EID: 84921519720     PISSN: 00142980     EISSN: 15214141     Source Type: Journal    
DOI: 10.1002/eji.201444453     Document Type: Article

References (40)

1. Svendsen, A. J., Holm, N. V., Kyvik, K., Petersen, P. H. and Junker, P., Relative importance of genetic effects in rheumatoid arthritis: historical cohort study of Danish nationwide twin population. Br. Med. J. 2002. 324: 264-266.
2. Richardson, B., Scheinbart, L., Strahler, J., Gross, L., Hanash, S. and Johnson, M., Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 1990. 33: 1665-1673.
3. Karouzakis, E., Gay, R. E., Gay, S. and Neidhart, M., Increased recycling of polyamines is associated with global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2012. 64: 1809-1817.
4. Nile, C. J., Read, R. C., Akil, M., Duff, G. W. and Wilson, A. G., Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum. 2008. 58: 2686-2693.
5. Nakano, K., Whitaker, J. W., Boyle, D. L., Wang, W. and Firestein, G. S., DNA methylome signature in rheumatoid arthritis. Ann. Rheum. Dis. 2013. 72: 110-117.
6. Whitaker, J. W., Shoemaker, R., Boyle, D. L., Hillman, J., Anderson, D., Wang, W. and Firestein, G. S., An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype. Genome Med. 2013. 5: 40-51.
7. Liu, Y., Aryee, M. J., Padyukov, L., Fallin, M. D., Hesselberg, E., Runarsson, A., Reinius, L. et al., Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat. Biotechnol. 2013. 31: 142-147.
8. + regulatory T cells in immunological tolerance to self and non-self. Nat. Immunol. 2005. 6: 345-352.
9. + regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 2001. 182: 18-32.
10. van Amelsfort, J. M., Jacobs, K. M., Bijlsma, J. W., Lafeber, F. P. and Taams, L. S., CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum. 2004. 50: 2775-2785.
11. + T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin. Exp. Immunol. 2005. 140: 360-367.
12. Ehrenstein, M. R., Evans, J. G., Singh, A., Moore, S., Warnes, G., Isenberg, D. A. and Mauri, C., Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J. Exp. Med. 2004. 200: 277-285.
13. Flores-Borja, F., Jury, E. C., Mauri, C. and Ehrenstein, M. R., Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 2008. 105: 19396-19401.
14. Beavis, P. A., Gregory, B., Green, P., Cribbs, A. P., Kennedy, A., Amjadi, P., Palfreeman, A. C. et al., Resistance to regulatory T cell-mediated suppression in rheumatoid arthritis can be bypassed by ectopic foxp3 expression in pathogenic synovial T cells. Proc. Natl. Acad. Sci. USA 2011. 108: 16717-16722.
15. Hori, S., Nomura, T. and Sakaguchi, S., Control of regulatory T cell development by the transcription factor Foxp3. Science 2003. 299: 1057-1061.
16. Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E. et al., The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 2001. 27: 20-21.
17. Baron, U., Floess, S., Wieczorek, G., Baumann, K., Grutzkau, A., Dong, J., Thiel, A. et al., DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur. J. Immunol. 2007. 37: 2378-2389.
18. Polansky, J. K., Kretschmer, K., Freyer, J., Floess, S., Garbe, A., Baron, U., Olek, S. et al., DNA methylation controls Foxp3 gene expression. Eur. J. Immunol. 2008. 38: 1654-1663.
19. Janson, P. C., Winerdal, M. E., Marits, P., Thorn, M., Ohlsson, R. and Winqvist, O., FOXP3 promoter demethylation reveals the committed Treg population in humans. PLoS One 2008. 3: e1612.
20. Mantel, P. Y., Ouaked, N., Ruckert, B., Karagiannidis, C., Welz, R., Blaser, K. and Schmidt-Weber, C. B., Molecular mechanisms underlying FOXP3 induction in human T cells. J. Immunol. 2006. 176: 3593-3602.
21. Ruan, Q., Kameswaran, V., Tone, Y., Li, L., Liou, H. C., Greene, M. I., Tone, M. et al., Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome. Immunity 2009. 31: 932-940.
22. Lal, G., Zhang, N., van der Touw, W., Ding, Y., Ju, W., Bottinger, E. P., Reid, S. P. et al., Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J. Immunol. 2009. 182: 259-273.
23. Okano, M., Bell, D. W., Haber, D. A. and Li, E., DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999. 99: 247-257.
24. Ballestar, E., Epigenetic alterations in autoimmune rheumatic diseases. Nat. Rev. Rheumatol. 2011. 7: 263-271.
25. Barzaghi, F., Passerini, L., Gambineri, E., Ciullini Mannurita, S., Cornu, T., Kang, E. S., Choe, Y. H. et al., Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome. J. Autoimmun. 2012. 38: 49-58.
26. Tatura, R., Zeschnigk, M., Adamzik, M., Probst-Kepper, M., Buer, J. and Kehrmann, J., Quantification of regulatory T cells in septic patients by real-time PCR-based methylation assay and flow cytometry. PLoS One 2012. 7: e49962.
27. Wieczorek, G., Asemissen, A., Model, F., Turbachova, I., Floess, S., Liebenberg, V., Baron, U. et al., Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer Res. 2009. 69: 599-608.
28. +CD25(hi) regulatory cells in patients with multiple sclerosis. J. Immunol. 2011. 186: 3317-3326.
29. Lucas, S., van Baren, N., de Smet, C. and Coulie, P. G., Demethylation of the FOXP3 gene in human melanoma cells precludes the use of this epigenetic mark for quantification of Tregs in unseparated melanoma samples. Int. J. Cancer 2012. 130: 1960-1966.
30. + regulatory T cells in the human immune system. Nat. Rev. Immunol. 2010. 10: 490-500.
31. Ohkura, N., Hamaguchi, M., Morikawa, H., Sugimura, K., Tanaka, A., Ito, Y., Osaki, M. et al., T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 2012. 37: 785-799.
32. Kim, Y. I., Logan, J. W., Mason, J. B. and Roubenoff, R., DNA hypomethylation in inflammatory arthritis: reversal with methotrexate. J. Lab. Clin. Med. 1996. 128: 165-172.
33. Liu, C. C., Fang, T. J., Ou, T. T., Wu, C. C., Li, R. N., Lin, Y. C., Lin, C. H. et al., Global DNA methylation, DNMT1, and MBD2 in patients with rheumatoid arthritis. Immunol. Lett. 2011. 135: 96-99.
34. + T cells of patients with systemic lupus erythematosus. Clin. Rheumatol. 2008. 27: 21-27.
35. + T cells from patients with systemic lupus erythematosus, systemic sclerosis, and dermatomyositis. Scand. J. Rheumatol. 2009. 38: 369-374.
36. Nakano, K., Boyle, D. L. and Firestein, G. S., Regulation of DNA methylation in rheumatoid arthritis synoviocytes. J. Immunol. 2013. 190: 1297-1303.
37. Nishimura, K., Sugiyama, D., Kogata, Y., Tsuji, G., Nakazawa, T., Kawano, S., Saigo, K. et al., Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann. Intern. Med. 2007. 146: 797-808.
38. Aletaha, D., Alasti, F. and Smolen, J. S., Rheumatoid factor determines structural progression of rheumatoid arthritis dependent and independent of disease activity. Ann. Rheum. Dis. 2013. 72: 875-880.
39. Vittecoq, O., Pouplin, S., Krzanowska, K., Jouen-Beades, F., Menard, J. F., Gayet, A., Daragon, A. et al., Rheumatoid factor is the strongest predictor of radiological progression of rheumatoid arthritis in a three-year prospective study in community-recruited patients. Rheumatology (Oxford) 2003. 42: 939-946.
40. Creusot, F., Acs, G. and Christman, J. K., Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2'-deoxycytidine. J. Biol. Chem. 1982. 257: 2041-2048.