Epigenetic mechanisms in multiple sclerosis: implications for pathogenesis and treatment

Abstract

Clinical neurologists and scientists who study multiple sclerosis face open questions regarding the integration of epidemiological data with genome-wide association studies and clinical management of patients. It is becoming evident that the interplay of environmental influences and individual genetic susceptibility modulates disease presentation and therapeutic responsiveness. The molecular mechanisms through which environmental signals are translated into changes in gene expression include DNA methylation, post-translational modification of nucleosomal histones, and non-coding RNAs. These mechanisms are regulated by families of specialised enzymes that are tissue selective and cell-type specific. A model of multiple sclerosis pathogenesis should integrate underlying risk related to genetic susceptibility with cell-type specific epigenetic changes occurring in the immune system and in the brain in response to ageing and environmental stimuli.

Figure 1. Epigenetic mechanisms regulating transcription

The human genome is tightly packed into the nucleus via wrapping around histones and chromatin compaction. The on and off state of gene expression is governed by DNA accessibility and epigenetic marks. The balance between these two states is modulated by DNA methylation, post-translational modification, and microRNAs. Theoctameric structure of nucleosomes, composed of dimers of H2A, H2B, H3, and H4 subunits, is shown Histone HI, by contrast, is not part of the nucleosome but serves as a linker.

Figure 2. Major post-translational modifications on histonetails

Post-translational modifications of lysine (K), arginine (R), serine (S), and threonine (T) residues are shown with their respective modifying enzymes. Arginine residues can be methylated symmetrically or asymmetrically; lysine residues can be monomethylated, dimethylated,ortrimethylated. Enzymes shown in green are associated with transcriptional activation (table 1), and enzymes shown in red are associated with transcriptional repression (table 2).

Figure 3. Environmental stimuli influence gene expression through epigenetic mechanisms

Putative environmental insults associated with multiple sclerosis alter the epigenetic landscape, which can ultimately affect gene expression in a cell-specific manner. These changes can affect disease onset or progression, depending on the timing of the accumulating stimuli. Environmental signals that affect human disease are shown in blue, evidence of an environmental effect from animal studies in purple, and the molecular mechanisms responsible for outcomes are in red.