Demethylation of CD40LG on the inactive X in T cells from women with lupus.
Why systemic lupus erythematosus primarily affects women is unknown. Recent evidence indicates that human lupus is an epigenetic disease characterized by impaired T cell DNA methylation. Women have two X chromosomes; one is inactivated by mechanisms including DNA methylation. We hypothesized that demethylation of sequences on the inactive X may cause gene overexpression uniquely in women, predisposing them to lupus. We therefore compared expression and methylation of CD40LG, a B cell costimulatory molecule encoded on the X chromosome, in experimentally demethylated T cells from men and women and in men and women with lupus. Controls included TNFSF7, a methylation-sensitive autosomal B cell costimulatory molecule known to be demethylated and overexpressed in lupus. Bisulfite sequencing revealed that CD40LG is unmethylated in men, while women have one methylated and one unmethylated gene. 5-Azacytidine, a DNA methyltransferase inhibitor, demethylated CD40LG and doubled its expression on CD4(+) T cells from women but not men, while increasing TNFSF7 expression equally between sexes. Similar studies demonstrated that CD40LG demethylates in CD4(+) T cells from women with lupus, and that women but not men with lupus overexpress CD40LG on CD4(+) T cells, while both overexpress TNFSF7. These studies demonstrate that regulatory sequences on the inactive X chromosome demethylate in T cells from women with lupus, contributing to CD40LG overexpression uniquely in women. Demethylation of CD40LG and perhaps other genes on the inactive X may contribute to the striking female predilection of this disease.
Lu
Qianjin
Q
Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, 41011 Hunan, China.
Wu
Ailing
A
Tesmer
Laura
L
Ray
Donna
D
Yousif
Neda
N
Richardson
Bruce
B
D000328:Adult; D053282:CD27 Ligand / Q000235:genetics; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008297:Male; D008745:Methylation; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012727:Sex Characteristics; D013601:T-Lymphocytes / Q000276:immunology*; D049951:X Chromosome Inactivation / Q000235:genetics*
D053282:CD27 Ligand; C505771:CD70 protein, human; D012333:RNA, Messenger; D023201:CD40 Ligand; D004247:DNA