17β-oestradiol enhances global DNA hypomethylation in CD4-positive T cells from female patients with lupus, through overexpression of oestrogen receptor-α-mediated downregulation of DNMT1.

Abstract

Systemic lupus erythematosus (SLE) affects primarily women, and oestrogen appears to play a significant role in SLE development. Our previous studies showed that inhibition of DNA methyltransferase 1 (DNMT1) enhanced global DNA hypomethylation in CD4+ T cells isolated from patients with SLE, and exacerbated SLE. However, the effects of 17β-oestradiol on global DNA hypomethylation and DNMT1 expression in CD4+ T cells of female patients with SLE remain largely unknown. To investigate the ability of 17β-oestradiol to affect global DNA methylation in female SLE CD4+ T cells and the mechanism(s) underlying this ability. We enrolled 30 women with SLE and 15 controls. CD4+ T cells exposed to 17β-oestradiol were analysed by global DNA methylation measurements, western blotting and real-time PCR. Plasma 17β-oestradiol levels were measured by ELISA. In female SLE CD4+ T cells, 17β-oestradiol downregulated DNMT1 expression at both the mRNA and protein levels, and enhanced global DNA hypomethylation. Plasma 17β-oestradiol levels were similar in patients with SLE and controls. The mRNA expression of oestrogen receptor (ER)α, but not of ERβ, was upregulated in SLE CD4+ T cells. Furthermore, the 17β-oestradiol-induced downregulation of DNMT1 expression and global DNA hypomethylation were rescued by an ER antagonist. 17β-oestradiol enhances global DNA hypomethylation in female SLE CD4+ T cells via downregulation of DNMT1 mediated by ERα overexpression.