Ethnic Differences in DNA Methyltransferases Expression in Patients with Systemic Lupus Erythematosus
Systemic lupus erythematous (SLE) is a systemic autoimmune inflammatory disease with both genetic and epigenetic etiologies. Evidence suggests that deregulation of specific genes through epigenetic mechanisms may be a contributing factor to SLE pathology. There is increasing evidence that DNA methyltransferase activity may be involved. This study demonstrated modulation in expression of DNA methyltransferases (DNMTs) according to ethnicity in patients diagnosed with SLE. Furthermore, differential expression in one of the DNMTs was found in a subset of lupus patients on dehydroepiandrosterone (DHEA) therapy.
Real-time PCR analyses of DNMT1, DNMT3A and DNMT3B in peripheral blood mononuclear cells from a cohort of African American and European American lupus and non-lupus women were conducted. Also, global DNA methylation was assessed using the MethylFlashTM methylated quantification colorimetric assay.
Significant increase in DNMT3A (p < 0.001) was shown in lupus patients when compared to age-matched healthy controls. This increase was associated with a higher SLEDI index. More striking was that expression levels for African American (AA) women were higher than European American women in the lupus populations. A subset of AA women on DHEA therapy showed a significant decrease (p < 0.05) in DNMT3A expression in comparison to lupus patients not on the therapy. DHEA is an androgenic steroid found in low levels in the serum of lupus patients. Supplementation of this hormone has been shown to be beneficial to some lupus patients. DHEA was not shown to effect DNMT1 or DNMT3B expression. Increased expression was also noted in DNMT3B (p < 0.05) in lupus patients compared to age-matched healthy controls. However, no significant difference was noted in DNMT1 (p = 0.2148) expression between lupus patients and healthy controls. Although increases were detected in de novo methyltransferases, a global decrease (p < 0.001) in 5-methycytosine was observed in lupus patients when compared to age-matched healthy controls.
These findings suggest that epigenetic changes may play a critical role in the manifestations of the disease observed among ethnic groups, particularly African American women who often have a higher incidence of lupus. DHEA therapy effects on DNMT3A expression in AA women warrant further investigation in a larger population.
- Lahita, RG (2004) Systemic lupus erythematosus. Elsevier, Amsterdam
- Lupus Foundation of American. Statistics about Lupus.
- Foundation, S.L.E.L., Facts about gender and racial disparities in Lupus: Lupus targest women and minorities.
- Ramos-Casals, M (2008) A systematic review of the off-label use of biological therapies in systemic autoimmune diseases. Med. (Baltimore) 87: pp. 345-364 CrossRef
- Murray, E, Perry, M (2010) Off-label use of rituximab in systemic lupus erythematosus: a systematic review. Clin Rheumatol 29: pp. 707-716 CrossRef
- Calero, I, Sanz, I (2010) Targeting B cells for the treatment of SLE: the beginning of the end or the end of the beginning?. Discov Med 10: pp. 416-424
- Kocis, P (2006) Prasterone. Am J Health Syst Pharm 63: pp. 2201-2210 CrossRef
- Merrill, JT (2003) Dehydroepiandrosterone, a sex steroid metabolite in development for systemic lupus erythematosus. Expert Opin Investig Drugs 12: pp. 1017-1025 CrossRef
- Ãstensen, M, Villiger, PM (2000) Nonsteroidal anti-inflammatory drugs in systemic lupus erythematosus. Lupus 9: pp. 566-572 CrossRef
- Jabin, D, Kumar, S, Gow, PJ (2010) Outcome of patients on azathioprine: a need for a better pre-treatment assessment and dosing guideline. N Z Med J 123: pp. 67-73
- Scheinfeld, N (2006) A review of rituximab in cutaneous medicine. Dermatol Online J 12: pp. 3
- Mitka, M (2011) Treatment for Lupus, first in 50 years, offers modest benefits, hope to patients. J Am Med Assoc 305: pp. 1754-1755 CrossRef
- Cunningham, M, Gilkeson, G (2011) Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol 40: pp. 66-73 CrossRef
- Sawalha, AH, Kovats, S (2008) Dehydroepiandrosterone in systemic lupus erythematous. Current Rheumatol Rep 10: pp. 286-291 CrossRef
- Luo, Y (2008) Abnormal DNA methylation in T cells from patients with subacute cutaneous lupus erythematosus. Br J Dermatol 159: pp. 827-833 CrossRef
- Ballestar, E, Esteller, M, Richardson, BC (2006) The epigentic face of systemi lupus erythematosus. J Immunol 176: pp. 143-147
- Richardson, B (1986) Effect of an inhibitor of DNA methylation on T cells. II. 5-Azacytidine induces self-reactivity in antigen-specific T4+ cells. Hum Immunol 17: pp. 456-470 CrossRef
- Zhou, Y (2009) T cell CD40LG gene expression and the production of IgG by autologous B cells in systemic lupus erythematosus. Clin Immunol 132: pp. 362-370 CrossRef
- Wei-Min, S (2009) The effect of DNMTs and MBPs on hypomethylation in systemic lupus erythematosus. J Dermatol Sci 53: pp. 236-238 CrossRef
- Fisher, CL, Fisher, AG (2011) Chromatin states in pluripotent, differentiated, and reprogrammed cells. Curr Opin Genet Dev 21: pp. 140-146 CrossRef
- Fitzpatrick, DR, Wilson, CB (2003) Methylation and demethylation in the regulation of genes, cells, and responses in the immune system. Clin Immunol 109: pp. 37-45 CrossRef
- Ehrlich, M (2003) The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease. Clin Immunol 109: pp. 17-28 CrossRef
- Balada, E, Ordi-Ros, J, Vilardell-Tarres, M (2007) DNA methylation and systemic lupus erythematosus. Ann N Y Acad Sci 1108: pp. 127-136 CrossRef
- Zouali, M (2011) Epigenetics in lupus. Ann N Y Acad Sci 1217: pp. 154-165 CrossRef
- Gowher, H (2005) De Novo Methylation of Nucleosomal DNA by the Mammalian Dnmt1 and Dnmt3A DNA Methyltransferasesâ€. Biochemistry 44: pp. 9899-9904 CrossRef
- Fatemi, M (2001) The activity of the murine DNA methyltransferase Dnmt1 is controlled by interaction of the catalytic domain with the N-terminal part of the enzyme leading to an allosteric activation of the enzyme after binding to methylated DNA. J Mol Biol 309: pp. 1189-1199 CrossRef
- Hedrich, CM, Tsokos, GC (2011) Epigenetic mechanims in systemic lupus erythematosus and other autoimmune diseases. Trends Mol Med 17: pp. 714-722 CrossRef
- Hughes, T, Sawalha, AH (2011) The role of epigenetic variation in the pathogenesis of systemic lupus erythematosus. Arthritis Res Ther 13: pp. 1-11
- Sckigawa, I, Okada, M, Ogasawara, H, Hishikawa, T, Hashimoto, H (2003) DNA methylation in systemic lupus erythematosus. Lupus 12: pp. 79-85 CrossRef
- Richardson, BC (2002) Role of DNA methylation in the regulation of cell function: autoimmune, aging and cancer. J Nutrition 132: pp. 2401-2405
- Zhao, S, Long, H, Lu, Q (2010) Epigenetic perspectives in systemic lupus erythematosus: pathogenesis, biomarkers, and therapeutic potentials. Clin Rev Allergy Immunol 39: pp. 3-9 CrossRef
- Marks, PA, Miller, T, Richon, VM (2003) Histone deacetylases. Curr Opin Pharmacol 3: pp. 344-351 CrossRef
- Astrid S, et al. The Emerging Therapeutic Potential of Histone Methyltransferase and Demethylase Inhibitors. ChemMedChem, 2009. 9999(9999): p. NA.
- Cunliffe, VT (2008) Eloquent silence: developmental functions of Class I histone deacetylases. Curr Opin Genet Dev 18: pp. 404-410 CrossRef
- Ng, K (2007) Xist and the order of silencing. EMBO Rep 8: pp. 34-39 CrossRef
- Cheng, X, Blumenthal, RM (2008) Mammalian DNA Methyltransferases: a structural perspective. Structure 16: pp. 341-350 CrossRef
- Jeffries, MA, Dozmorov, M, Tang, Y, Merrill, JT, Wren, JD, Sawalha, AH (2011) Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus. Epigenetics 6: pp. 593-601 CrossRef
- Lai, G, Bromberg, JS (2009) Eipigenetic mechanisms of regulation of Foxp3 expression. Blood 114: pp. 3727-3734 CrossRef
- Lu, Q, Wu, A, Richardson, BC (2005) Demethylaion of the same promoter sequence increaseas CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. J Immunol 174: pp. 6212-6219
- Lai, G, Zhang, N, Touw, W (2009) Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol 182: pp. 259-273
- Liu, CC (2011) Global DNA methylation, DNMT1, and MBD2 in patients with systemic lupus erythematosus. Lupus 20: pp. 131-136 CrossRef
- Zhu, X (2011) Analysis of associations between the patterns of global DNA hypomethylation and expression of DNA methyltransferase in patients with systemic lupus erythematosus. Int J Dermatol 50: pp. 697-704 CrossRef
- Nagar, M (2008) Epigenetic inheritance of DNA methylation limits activation-induced expression of FOXP3 in conventional human CD25âˆ’CD4+ T cells. Int Immunol 20: pp. 1041-1055 CrossRef
- Makar, KW (2003) Active recruitment of DNA methyltransferases regulates interleukin 4 in thymocytes and T cells. Nat Immunol 4: pp. 1183-1190 CrossRef
- Hodge, DR (2007) IL-6 Enhances the Nuclear Translocation of DNA Cytosine-5-Methyltransferase 1 (DNMT1) via Phosphorylation of the Nuclear Localization Sequence by the AKT Kinase. CANCER GENOMICS PROTEOMICS 4: pp. 387-398
- Schonthaler, HB, Guinea-Viniegra, J, Wagner, EF (2011) Targeting inflammation by modulating the Jun/AP-1 pathway. Ann Rheum Dis 70: pp. 1109-1112 CrossRef
- Ethnic Differences in DNA Methyltransferases Expression in Patients with Systemic Lupus Erythematosus
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Journal of Clinical Immunology
Volume 33, Issue 2 , pp 342-348
- Cover Date
- Print ISSN
- Online ISSN
- Springer US
- Additional Links
- DNA methyltransferases
- Industry Sectors