Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naïve CD4+ T cells from lupus patients (P4539)

• Published in: The Journal of immunology (1950) 2013-05, Vol.190 (1_Supplement), p.197-197.4
• Main Authors: Sawalha, Amr, Jeffries, Matlock, Altorok, Nezam, Dozmorov, Mikhail, Koelsch, Kristi, Wren, Jonathan, Merrill, Joan, McCune, W., Coit, Patrick
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.190.Supp.197.4

Abnormal T cell DNA methylation and type-1 interferon play an important role in the pathogenesis of systemic lupus erythematosus. We performed a genome-wide DNA methylation study in two independent sets of lupus patients and matched healthy controls to characterize the DNA methylome in naïve CD4+ T cells in lupus. DNA methylation was quantified for over 485,000 methylation sites across the genome, and differentially methylated sites between lupus patients and controls were identified and then independently replicated. Gene expression analysis was also performed from the same cells to investigate the relationship between the DNA methylation changes observed and mRNA expression levels. We identified and replicated 86 differentially methylated CG sites between patients and controls in 47 genes. Importantly, we observed significant hypomethylation in interferon-regulated genes in naïve T cells from lupus patients, suggesting epigenetic transcriptional accessibility of these genetic loci. The hypomethylation in interferon-regulated genes was not related to lupus disease activity. Gene expression analysis showed overexpression of these genes in total but not naïve CD4+ T cells from lupus patients. Our data suggest epigenetic “poising” of interferon-regulated genes in lupus naïve CD4+ T cells, argue for a novel pathogenic implication for abnormal T cell DNA methylation in lupus, and suggest a mechanism for type-1 interferon hyper-responsiveness in lupus T cells.