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

Abstract

Systemic lupus erythematosus is an autoimmune disease characterized by multi-system involvement and autoantibody production. Abnormal T cell DNA methylation and type-I interferon play an important role in the pathogenesis of lupus. 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, with the majority being hypomethylated. We observed significant hypomethylation in interferon-regulated genes in naïve T cells from lupus patients, including IFIT1, IFIT3, MX1, STAT1, IFI44L, USP18, TRIM22 and BST2, suggesting epigenetic transcriptional accessibility in these genetic loci. Indeed, the majority of the hypomethylated genes (21 out of 35 hypomethylated genes) are regulated by type I interferon. 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-I interferon hyper-responsiveness in lupus T cells.

Apoptotic cell-derived membrane microparticles and IFN-α induce an inflammatory immune response

“…STAT1 in particular has been associated with the development of, for example, lupus nephritis (Dong et al, 2007) and purpose anaemia (DominguezGutierrez et al, 2014) and also has been shown to be hypomethylated in CD4+ T-cells from lupus patients (Coit et al, 2013) as well as having higher expression in peripheral blood mononuclear cells (PBMCs) from SLE patients (Karonitsch et al, 2009). Our results show that the synergism observed between IFN-α and AdMP on inflammation is likely to be mediated by a readily increased phosphorylation and therefore higher transcriptional activity of STAT1.…”

Type I interferon–mediated autoimmune diseases: pathogenesis, diagnosis and targeted therapy

“…Although early studies reported elevated levels of IFN- in sera of SLE patients, the sensitivity of the method appears low, since IFN-I levels are either undetectable or dependent on several factors such as ethnic background, age, and sex (143)(144)(145)(146). Indirect methods were also used to measure IFN-I activity.…”

Epigenetic Alterations in Cellular Immunity: New Insights into Autoimmune Diseases

“…Recent studies applying sequence analysis technology have gained meaningful results that provide us with more information about lupus heritability [79], ethnicity variance [80] and renal involvement with DNA methylome analysis in CD4+ T cells [81]. Coit et al confirmed a group of interferon-related genes that are aberrantly hypomethylated, including IFN-induced protein 44-like (IFI44L), IFN-induced protein with tetratricopeptide (IFIT1), IFIT3, MX dynamin-like GTPase 1 (MX1), signal transducer and activator of transcription 1 (STAT-1), bone marrow stromal cell antigen 2 (BST2) and tripartite motif containing 22 (TRIM22), in lupus CD4+ T cells [82]. Furthermore, a newly identified IFN-related gene IFI44L has been deciphered in SLE, and the study also emphasized its potential role as a diagnostic biomarker [83].…”