Z Wu1, Y Sun, X Mei, C Zhang, W Pan, W Shi. 1. Department of Dermatology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Jiaotong University, Shanghai, China.
Abstract
BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 17β-oestradiol enhances global DNA hypomethylation in female SLE CD4+ T cells via downregulation of DNMT1 mediated by ERα overexpression.
BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 17β-oestradiol enhances global DNA hypomethylation in female SLE CD4+ T cells via downregulation of DNMT1 mediated by ERα overexpression.
Authors: Troy A Roepke; Ali Yasrebi; Alejandra Villalobos; Elizabeth A Krumm; Jennifer A Yang; Kyle J Mamounis Journal: Sci Rep Date: 2017-07-25 Impact factor: 4.379