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

ABSTRACT

Introduction: Multiple 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 (IFNß), was one of the first disease modifying therapies in multiple sclerosis (MS). However, how IFNß reduces disease burden in MS is not fully understood and little is known about the precise effect of IFNß treatment on methylation. Methods: The objective of this study was to determine the changes in DNAm associated with INFß use, using methylation arrays and statistical deconvolutions on two separate datasets (total ntreated = 64, nuntreated = 285). Results: We show that IFNß 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 IFNß treatment therapeutic lag. This suggests that methylation changes are required for treatment efficacy. Overrepresentation analysis found that IFNß treatment recruits the endogenous anti-viral molecular machinery. Finally, statistical deconvolution revealed that dendritic cells and regulatory CD4+ T cells were most affected by IFNß induced methylation changes. Discussion: In conclusion, our study shows that IFNß treatment is a potent and targeted epigenetic modifier in multiple sclerosis.