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.
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.


OBJECTIVE
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.
Department of Dermatology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Jiaotong University, Shanghai, China.
Z
Z
Wu
Y
Y
Sun
X
X
Mei
C
C
Zhang
W
W
Pan
W
W
Shi
D000328:Adult; D000704:Analysis of Variance; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects*; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D004958:Estradiol; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human