Increased DNA methylation of SLFN12 in CD4+ and CD8+ T cells from multiple sclerosis patients

Abstract

DNA methylation is an epigenetic mark that is influenced by environmental factors and is associated with changes to gene expression and phenotypes. It may link environmental exposures to disease etiology or indicate important gene pathways involved in disease pathogenesis. We identified genomic regions that are differentially methylated in T cells of patients with relapsing remitting multiple sclerosis (MS) compared to healthy controls. DNA methylation was assessed at 450,000 genomic sites in CD4+ and CD8+ T cells purified from peripheral blood of 94 women with MS and 94 healthy women, and differentially methylated regions were identified using bumphunter. Differential DNA methylation was observed near four loci: MOG/ZFP57, HLA-DRB1, NINJ2/LOC100049716, and SLFN12. Increased methylation of the first exon of the SLFN12 gene was observed in both T cell subtypes and remained present after restricting analyses to samples from patients who had never been on treatment or had been off treatment for more than 2.5 years. Genes near the regions of differential methylation in T cells were assessed for differential expression in whole blood samples from a separate population of 1,329 women with MS and 97 healthy women. Gene expression of HLA-DRB1, NINJ2, and SLFN12 was observed to be decreased in whole blood in MS patients compared to controls. We conclude that T cells from MS patients display regions of differential DNA methylation compared to controls, and corresponding gene expression differences are observed in whole blood. Two of the genes that showed both methylation and expression differences, NINJ2 and SLFN12, have not previously been implicated in MS. SLFN12 is a particularly compelling target of further research, as this gene is known to be down-regulated during T cell activation and up-regulated by type I interferons (IFNs), which are used to treat MS.

Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression

“…Likewise, our cell type-specific analyses demonstrated none and one significant DMP in CD4 + and CD8 + T cells between RRMS and controls, respectively, and no overlap with previous findings [[12], [13], [14],16]. However, we corroborated previously reported overall higher methylation in CD8 + T cells of RRMS patients [13,42]. Moreover, the top most variable positions, particularly in CD4 + T cells, segregated MS patients from controls, suggesting a lack of power to identify true underlying differences.…”

No differential gene expression for CD4+ T cells of MS patients and healthy controls

“…We showed significant DNA methylation differences in the HLA, MOG, NINJ2 and SLFN12 gene regions. 18 The HLA region was not considered in the current study, whereas the MOG gene was not expressed by the CD4 þ T cells. Both the NINJ2 and SLFN12 genes showed a non-significant trend towards lower gene expression.…”

Quantitative proteomic analyses of CD4+ and CD8+ T cells reveal differentially expressed proteins in multiple sclerosis patients and healthy controls

“…Both genome-wide studies on epigenetic modifications, such as DNA methylation, as well as transcriptomic analyses in immune cells have been conducted in order to investigate the potential dysregulation of immune cells in MS. Epigenetic profiling in peripheral blood mononuclear cells and in immune cell subtypes, i.e. CD4 + and CD8 + T cells, suggests global differences in DNA methylation between MS patients and healthy controls [8–12]. Of note, a few single genes displayed significant differential DNA methylation levels between MS patients and healthy controls, but no overlap, except for in the HLA-DRB1 locus [12, 13], was observed between the different studies [7].…”

“…CD4 + and CD8 + T cells, suggests global differences in DNA methylation between MS patients and healthy controls [8–12]. Of note, a few single genes displayed significant differential DNA methylation levels between MS patients and healthy controls, but no overlap, except for in the HLA-DRB1 locus [12, 13], was observed between the different studies [7]. Microarray analyses of blood from MS patients and healthy controls indicate dysregulation of T cell pathways during MS pathogenesis [14, 15].…”