Epigenetic effects of transmethylation micronutrients on gene expression in T cells from patients with active lupus. (116.12)

Abstract

Abstract T cell DNA demethylation contributes to the development of human lupus. However, the mechanisms causing T cell DNA demethylation in lupus patients are incompletely understood. The replication of DNA methylation patterns during mitosis depends on DNA methyltransferase (Dnmt) enzymatic activity and the methyl donor S-adenosylmethionine (SAM), and is inhibited by S-adenosylhomocysteine (SAH). SAM levels are determined by various dietary nutrients including folate and methionine, and previous work demonstrates that patients with active lupus patients have decreased Dnmt activity. We hypothesized that lupus patients will be more susceptible to environmental changes in folate and methionine due to their already low levels of T cell Dnmt activity compared to controls, resulting in aberrant overexpression of genes normally suppressed by DNA methylation. We cultured PHA-stimulated lupus T cells in media containing physiologic high and low concentrations of folate or methionine, and compared effects on methylation sensitive gene expression (CD11a, CD70, KIR and perforin) by flow cytometry. Lupus T cells cultured in lower concentrations of folate and methionine overexpress CD70, KIR and perforin compared to those cultured in standard RPMI 1640 media, relative to control T cells. These results suggest that folate and methionine may contribute to abnormal T cell gene expression in lupus, and that dietary supplementation may have a beneficial effect.