title: Overexpression of X-linked genes in T cells from women with lupus.
abstract: Women develop lupus more frequently than men and the reason remains incompletely understood. Evidence that men with Klinefelter's Syndrome (XXY) develop lupus at approximately the same rate as women suggests that a second X chromosome contributes. However, since the second X is normally inactivated, how it predisposes to lupus is unclear. DNA methylation contributes to the silencing of one X chromosome in women, and CD4+ T cell DNA demethylation contributes to the development of lupus-like autoimmunity. This suggests that demethylation of genes on the inactive X may predispose women to lupus, and this hypothesis is supported by a report that CD40LG, an immune gene encoded on the X chromosome, demethylates and is overexpressed in T cells from women but not men with lupus. Overexpression of other immune genes on the inactive X may also predispose women to this disease. We therefore compared mRNA and miRNA expression profiles in experimentally demethylated T cells from women and men as well as in T cells from women and men with lupus. T cells from healthy men and women were treated with the DNA methyltransferase inhibitor 5-azacytidine, then X-linked mRNAs were surveyed with oligonucleotide arrays, and X-linked miRNA's surveyed with PCR arrays. CD40LG, CXCR3, OGT, miR-98, let-7f-2*, miR 188-3p, miR-421 and miR-503 were among the genes overexpressed in women relative to men. MiRNA target prediction analyses identified CBL, which downregulates T cell receptor signaling and is decreased in lupus T cells, as a gene targeted by miR-188-3p and miR-98. Transfection with miR-98 and miR-188-3p suppressed CBL expression. The same mRNA and miRNA transcripts were also demethylated and overexpressed in CD4+ T cells from women relative to men with active lupus. Together these results further support a role for X chromosome demethylation in the female predisposition to lupus.
authors: Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109-2200, USA. anurah@umich.edu
authors: Anura
authors: A
authors: Hewagama
authors: Gabriela
authors: G
authors: Gorelik
authors: Dipak
authors: D
authors: Patel
authors: Punsisi
authors: P
authors: Liyanarachchi
authors: W Joseph
authors: WJ
authors: McCune
authors: Emily
authors: E
authors: Somers
authors: Tania
authors: T
authors: Gonzalez-Rivera
authors: Faith
authors: F
authors: Strickland
authors: Bruce
authors: B
authors: Richardson
mesh_terms: D000328:Adult; D001374:Azacitidine / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D019175:DNA Methylation / Q000276:immunology; D005260:Female; D050172:Genes, X-Linked / Q000235:genetics / Q000276:immunology*; D006801:Humans; D015151:Immunoblotting; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D059467:Transcriptome / Q000276:immunology
chemical_list: C515187:CXCR3 protein, human; C584093:MIRN188 microRNA, human; C546084:MIRN98 microRNA, human; D035683:MicroRNAs; D054367:Receptors, CXCR3; D023201:CD40 Ligand; D050721:Proto-Oncogene Proteins c-cbl; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C067419:CBL protein, human; D001374:Azacitidine