Interferon beta treatment is a potent and targeted epigenetic modifier in multiple sclerosis

IntroductionMultiple Sclerosis (MS) has a complex pathophysiology that involves genetic and environmental factors. DNA methylation (DNAm) is one epigenetic mechanism that can reversibly modulate gene expression. Cell specific DNAm changes have been associated with MS, and some MS therapies such as dimethyl fumarate can influence DNAm. Interferon Beta (IFN beta), was one of the first disease modifying therapies in multiple sclerosis (MS). However, how IFN beta reduces disease burden in MS is not fully understood and little is known about the precise effect of IFN beta treatment on methylation. MethodsThe objective of this study was to determine the changes in DNAm associated with INF beta use, using methylation arrays and statistical deconvolutions on two separate datasets (total n(treated) = 64, n(untreated) = 285). ResultsWe show that IFN beta treatment in people with MS modifies the methylation profile of interferon response genes in a strong, targeted, and reproducible manner. Using these identified methylation differences, we constructed a methylation treatment score (MTS) that is an accurate discriminator between untreated and treated patients (Area under the curve = 0.83). This MTS is time-sensitive and in consistent with previously identified IFN beta treatment therapeutic lag. This suggests that methylation changes are required for treatment efficacy. Overrepresentation analysis found that IFN beta treatment recruits the endogenous anti-viral molecular machinery. Finally, statistical deconvolution revealed that dendritic cells and regulatory CD4+ T cells were most affected by IFN beta induced methylation changes. DiscussionIn conclusion, our study shows that IFN beta treatment is a potent and targeted epigenetic modifier in multiple sclerosis.

Automated summary

This study shows that IFN beta treatment modifies the methylation profile of interferon response genes in MS patients, and a methylation treatment score (MTS) was constructed to accurately distinguish between treated and untreated patients. The study also found that IFN beta treatment recruits the endogenous anti-viral molecular machinery and affects the methylation levels of dendritic cells and regulatory CD4+ T cells.