tSystemic lupus erythematosus (SLE) is a systemic autoimmune disease primarily affecting women. Pre-vious studies have indicated that sex hormone estrogens contribute to the female predilection of SLE.Estrogen regulates gene expression by translocating estrogen receptors (ER) and into the nucleuswhere they induce transcription by binding to estrogen response elements of target genes. We have pre-viously observed that expression of ER gene and protein in lupus patients is significantly higher thanin healthy controls and that estradiol up-regulates calcineurin expression via over-expression of ERgene in SLE. However, the pathogenesis of over-expression of ER gene is unknown. Here we report thatenhanced expression of ER mRNA and protein in SLE and rheumatoid arthritis is associated with DNAdemethylation within the proximal promoter region located between −232 and +81 base pair relativeto transcription start site of human ER gene (GenBank Accession no. AL356311.6). The frequency ofDNA demethylation was comparable between male and female. These findings suggest that estrogen anddemethylated ER promoter associated up-regulated ER genes are two critical factors in the genderbiased development of autoimmune diseases besides genetic factor.
