Epigenetic changes in multiple sclerosis: Effects of DNA methylation
The complex genetics of multiple sclerosis (MS) suggest that the balance between the genetic component and the epigenome is highly relevant in the susceptibility, onset, and progression of the disease.1 Epigenetic mechanisms at the molecular level include histone modifications, regulation of non-coding RNAs, and DNA methylation.1 At MSVirtual2020, the 8th Joint ACTRIMS-ECTRIMS Meeting held 9–13 September 2020, Professor Patrizia Casaccia (Icahn School of Medicine at Mount Sinai, New York, USA) provided an in-depth look at epigenomic changes that relate to MS, with a focus on DNA methylation.
Zeroing in on DNA methylation
Epigenetic changes can involve modifications of histones, which interact with DNA, or modification directly on nucleic acids. Both of these types of changes play a role in MS pathology. In her presentation at this year’s MSVirtual congress, Prof. Casaccia focused on DNA methylation.
Prof. Casaccia explained that DNA methylation refers to the addition of methyl groups at the level of specific cytosine residues. She remarked that when DNA methylation is low, there are high levels of gene expression, especially in the promotor region of genes, and when DNA methylation is high at the level of the promotor, this leads to low gene expression.
In her presentation, Prof. Casaccia focused on three studies from her laboratory that have helped her better understand the role of DNA methylation in MS.2-4
Gene expression and DNA methylation in NAWM
In the first study, Prof. Casaccia wanted to define the functional implication of DNA methylation and gene expression in the normal-appearing white matter (NAWM) of post‑mortem brain samples from patients with MS compared with controls. She explained that since epigenetic changes can be driven by lifestyle factors, there could be changes in white matter that render it much more susceptible to the disease process.
Prof. Casaccia summarized the results of the study; she and her researchers could see low levels of DNA methylation and increased gene expression in genes that encode for molecules that regulate antigenic processing. She noted that, in contrast, they detectedhigh levels of DNA methylation in genes that were decreasing in expression, especially in the brains of patients with MS. She explained that many of the genes that were decreasing in expression, such as NDRG1 (N-Myc Downstream Gene 1), are oligodendrocyte genes. Prof. Casaccia noted that functions of these genes were unknown until further studies, which are currently unpublished, showed that the genes are involved in remyelination. Inflammatory demyelination is one of the key characteristics of MS, so this latest finding confirms that the decrease in expression of oligodendrocyte genes was relevant to the effects of DNA methylation.4
DNA methylation in CD4+ T Cells
Next, Prof. Casaccia aimed to identify differential DNA methylation in CD4+ T cells sorted from the blood of patients treated for MS compared with untreated patients. She noted that these immunomodulators may differentially modify the epigenomic marks in T cells.
Prof. Casaccia shared data and models that illustrated the main finding of the study; that in patients treated for MS, there is induction of methylation at loci involved in T cell differentiation. This induction leads to a decrease of expression of the C-C Motif Chemokine Receptor 6 (CCR6) gene, which leads to a loss of the pathogenic CD4+ T cells in MS.3 She concluded that the treatment must lead to a loss in pathogenic phenotype.
Effect of BMI on RRMS: DNA methylation in monocytes
Lastly, Prof. Casaccia sought to define patterns of DNA methylation in monocytes sorted from the blood of patients with relapsing-remitting (RR) MS. She reiterated that lifestyle factors, including diet, may affect not only the disease onset, but also the disease course of MS.
As such, the study in question addressed the impact of body mass index (BMI) on the epigenome of monocytes and disease course in MS.4 Prof. Casaccia stated that the results of the study suggested that changes in lifestyle factors (i.e. diet) affect the lipid composition in the blood. In closing, she remarked that this change in lipid composition results in epigenetic changes in the nuclei of monocytes that can lead to potential worsened clinical disability.
Session in summary
Overall, Prof. Casaccia emphasized the role of epigenetic mechanisms in the pathology of MS, highlighting studies in which her group explored the effect of DNA methylation on gene expression in NAWM, treatment options through T cells, and the effects of diet and lifestyle through monocytes. Future studies expanding on these topics should give us a better understanding of the onset and progression of MS, as well as how to treat this debilitating disease.
Gacias M, Casaccia P. Epigenetic Mechanisms in Multiple Sclerosis. Revista Española de Esclerosis Múltiple 2014;6:25-35.
Huynh JL, Garg P, Thin TH. Epigenome-wide differences in pathology-free regions of multiple sclerosis–affected brains. Nature Neuroscience 2014;17:121-30.
Ntranos A, Ntranos V, Bonnefil V. Fumarates target the metabolic-epigenetic interplay of brain-homing T cells in multiple sclerosis. Brain 2019;142:647-61.
Castro K, Nstranos A, Amatruda M. Body Mass Index in Multiple Sclerosis modulates ceramide-induced DNA methylation and disease course. EBioMedicine 2019;43:392-410
