Genome-Wide Analysis of DNA Methylation in Cd4+ T Lymphocytes of Patients with Primary Progressive Multiple Sclerosis Indicates Involvement of This Epigenetic Process in the Disease Immunopathogenesis

Abstract

The pathogenesis of multiple sclerosis (MS), a chronic disease of the CNS, includes autoimmune and neurodegenerative components. In most cases, patients develop relapsing-remitting MS (RRMS), while 10-15% of patients develop primary progressive MS (PPMS), which differs from RRMS in the mechanisms of the pathological process, some demographic, and some clinical characteristics. These differences may be explained by the epigenetic regulation of gene expression in PPMS including DNA methylation as one of the key epigenetic processes. The features of DNA methylation in various cell populations in PPMS patients remain understudied. The goal of this study is to identify differentially methylated CpG sites (DMSs) of the genome of CD4+ T lymphocytes, which characterize PPMS. The study included eight treatment-naive PPMS patients and eight healthy controls. Genome-wide analysis of DNA methylation of CD4+ T lymphocytes was performed using high-density DNA microarrays. We have identified 108 DMSs, which distinguish PPMS patients from healthy controls. In PPMS patients 81% of the DMSs are hypermethylated. More than a half of the identified DMSs are located in known genes in CpG islands and adjacent regions, which indicates a high functional significance of these DMSs in PPMS development. Analysis of the overrepresentation of DMS-containing genes in the main biological processes demonstrates their involvement in the regulation of cell adhesion to the extracellular matrix and the development of the immune response, i.e., antigen processing and presentation, and development of the immune system. Genome-wide analysis of DNA methylation in CD4+ T lymphocytes of PPMS patients indicates the involvement of this epigenetic process in the immunopathogenesis of the disease. These results may help better understand the pathogenesis of this severe form of MS.