title: Demethylation within the proximal promoter region of human estrogen receptor alpha gene correlates with its enhanced expression: Implications for female bias in lupus.
abstract: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease primarily affecting women. Previous studies have indicated that sex hormone estrogens contribute to the female predilection of SLE. Estrogen regulates gene expression by translocating estrogen receptors (ER) α and β into the nucleus where they induce transcription by binding to estrogen response elements of target genes. We have previously observed that expression of ERα gene and protein in lupus patients is significantly higher than in healthy controls and that estradiol up-regulates calcineurin expression via over-expression of ERα gene in SLE. However, the pathogenesis of over-expression of ERα gene is unknown. Here we report that enhanced expression of ERα mRNA and protein in SLE and rheumatoid arthritis is associated with DNA demethylation within the proximal promoter region located between -232 and +81 base pair relative to transcription start site of human ERα gene (GenBank Accession no. AL356311.6). The frequency of DNA demethylation was comparable between male and female. These findings suggest that estrogen and demethylated ERα promoter associated up-regulated ERα genes are two critical factors in the gender biased development of autoimmune diseases besides genetic factor.
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Medicine, Antai Tian-Sheng Memorial Hospital, Pingtung, Taiwan; Division of Allergy, Immunology and Rheumatology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: liuhow@kmu.edu.tw.
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Liu
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Food science and Nutrition, Meiho University, Pingtung, Taiwan.
authors.forename: Hui-Li
authors.initials: HL
authors.lastname: Lin
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jeng-Hsien
authors.initials: JH
authors.lastname: Yen
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wen-Chan
authors.initials: WC
authors.lastname: Tsai
authors.affiliation: Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shyh-Shin
authors.initials: SS
authors.lastname: Chiou
authors.affiliation: Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Laboratory Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jan-Gowth
authors.initials: JG
authors.lastname: Chang
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Tsan-Teng
authors.initials: TT
authors.lastname: Ou
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Cheng-Chin
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Nien-Chan
authors.initials: NC
authors.lastname: Chao
mesh_terms: D000107:Acetylation; D000293:Adolescent; D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006657:Histones / Q000378:metabolism; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D047628:Estrogen Receptor alpha; D006657:Histones
keywords: Estrogen; Estrogen receptor alpha; Female bias; Promoter demethylation; Rheumatoid arthritis; Systemic lupus erythematosus