Multiple sclerosis (MS), a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system, is today a leading cause of unpredictable lifelong disability in young adults. The treatment of patients in progressive stages remains highly challenging, alluding to our limited understanding of the underlying pathological processes. In this review, we provide insights into the mechanisms underpinning MS progression from a perspective of epigenetics, that refers to stable and mitotically heritable, yet reversible, changes in the genome activity and gene expression. We first recapitulate findings from epigenetic studies examining the brain tissue of progressive MS patients, which support a contribution of DNA and histone modifications in impaired oligodendrocyte differentiation, defective myelination/remyelination and sustained neuro‐axonal vulnerability. We next explore possibilities for identifying factors affecting progression using easily accessible tissues such as blood by comparing epigenetic signatures in peripheral immune cells and brain tissue. Despite minor overlap at individual methylation sites, nearly 30% of altered genes reported in peripheral immune cells of progressive MS patients were found in brain tissue, jointly converging on alterations of neuronal functions. We further speculate about the mechanisms underlying shared epigenetic patterns between blood and brain, which likely imply the influence of internal (genetic control) and/or external (e.g. smoking and ageing) factors imprinting a common signature in both compartments. Overall, we propose that epigenetics might shed light on clinically relevant mechanisms involved in disease progression and open new avenues for the treatment of progressive MS patients in the future.

中文翻译：

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对多发性硬化症疾病进展的表观遗传学见解。

多发性硬化症（MS）是中枢神经系统的一种慢性炎症性脱髓鞘和神经退行性疾病，如今已成为年轻人不可预测的终生残疾的主要原因。由于我们对潜在病理过程的了解有限，因此进展期患者的治疗仍然具有很高的挑战性。在这篇综述中，我们从表观遗传学的角度提供了支持MS进展的机制的见解，表观遗传学是指基因组活性和基因表达的稳定且有丝分裂可遗传但可逆的变化。我们首先概括表观遗传学研究的结果，这些研究检查了进行性MS患者的脑组织，这些研究支持DNA和组蛋白修饰在少突胶质细胞分化受损中的作用，髓鞘变性/髓鞘再生不良和持续的神经轴突脆弱性。接下来，我们将通过比较外周免疫细胞和脑组织中的表观遗传学特征，探索使用诸如血液等易于获取的组织来鉴定影响进展的因素的可能性。尽管在各个甲基化位点上有微小的重叠，但在脑组织中发现了进行性MS患者外周免疫细胞中报道的近30％的基因改变，共同收敛于神经元功能的改变。我们进一步推测了血液和大脑之间共享表观遗传模式的潜在机制，这可能暗示着内部（遗传控制）和/或外部（例如吸烟和衰老）因素在两个隔室中都印有共同特征的影响。总体，