Abstract
Aims/hypothesisType 1 diabetes is a chronic autoimmune disease of complex aetiology, including a potential role for epigenetic regulation. Previous epigenomic studies focused mainly on clinically diagnosed individuals. The aim of the study was to assess early DNA methylation changes associated with type 1 diabetes already before the diagnosis or even before the appearance of autoantibodies.MethodsReduced representation bisulphite sequencing (RRBS) was applied to study DNA methylation in purified CD4+ T cell, CD8+ T cell and CD4−CD8− cell fractions of 226 peripheral blood mononuclear cell samples longitudinally collected from seven type 1 diabetes-specific autoantibody-positive individuals and control individuals matched for age, sex, HLA risk and place of birth. We also explored correlations between DNA methylation and gene expression using RNA sequencing data from the same samples. Technical validation of RRBS results was performed using pyrosequencing.ResultsWe identified 79, 56 and 45 differentially methylated regions in CD4+ T cells, CD8+ T cells and CD4−CD8− cell fractions, respectively, between type 1 diabetes-specific autoantibody-positive individuals and control participants. The analysis of pre-seroconversion samples identified DNA methylation signatures at the very early stage of disease, including differential methylation at the promoter of IRF5 in CD4+ T cells. Further, we validated RRBS results using pyrosequencing at the following CpG sites: chr19:18118304 in the promoter of ARRDC2; chr21:47307815 in the intron of PCBP3; and chr14:81128398 in the intergenic region near TRAF3 in CD4+ T cells.Conclusions/interpretationThese preliminary results provide novel insights into cell type-specific differential epigenetic regulation of genes, which may contribute to type 1 diabetes pathogenesis at the very early stage of disease development. Should these findings be validated, they may serve as a potential signature useful for disease prediction and management.Graphical abstract
Highlights
Type 1 diabetes is a complex autoimmune disease with a strong genetic component
No Gene Ontology (GO) terms were significantly enriched among the nearest genes for CD4+ T cells or CD4−CD8− cell fractions
representation bisulphite sequencing (RRBS) analysis of different cellular fractions identified methylation differences in children at risk for type 1 diabetes When including all the longitudinal samples into the differential methylation analysis model, we discovered 225, 114 and 87 differentially methylated CpG sites (DMCs) in the CD4+ T cell, CD8+ T cell and CD4−CD8− cell fractions, respectively, at FDR 0.1 (Fig. 2, Table 1, ESM Table 3–5)
Summary
Type 1 diabetes is a complex autoimmune disease with a strong genetic component. Genome-wide association studies (GWAS) have identified more than 60 genetic loci associated with the risk of type 1 diabetes [1,2,3]. Genetic variation alone cannot explain the conspicuous rise in the disease incidence during the past decades [4]. Several environmental factors, including viral infections, diet, toxins and other determinants, have been implicated [5]. Environmental exposures may result in epigenetic modifications of DNA, chromatin and histone proteins that change the level of gene expression. The importance of epigenetic gene regulation in complex disease phenotypes has been highlighted for several autoimmune disorders, such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) [6, 7]
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