Pirogov Russian National Research Medical University, 117997, Moscow, Ostrovityanova st. 1, Russia.
Pirogov Russian National Research Medical University, 117997, Moscow, Ostrovityanova st. 1, Russia.
Mult Scler Relat Disord. 2024 Nov;91:105910. doi: 10.1016/j.msard.2024.105910. Epub 2024 Sep 29.
Relapsing-remitting multiple sclerosis (RRMS) is a most common form of multiple sclerosis in which periods of neurological worsening are followed by periods of clinical remission. RRMS relapses are caused by an acute autoimmune inflammatory process, which can occur in any area of the central nervous system. Although development of exacerbation cannot yet be accurately predicted, various external factors are known to affect its risk. These factors may trigger the pathological process through epigenetic mechanisms of gene expression regulation, first of all, through changes in DNA methylation.
In the present work, we for the first time analyzed genome-wide DNA methylation patterns in CD4+ T lymphocytes and CD14+ monocytes of the same RRMS patients in relapse and remission. The effects of the differential methylation on gene expression were studied using qPCR.
We found 743 differentially methylated CpG positions (DMPs) in CD4+ cells and only 113 DMPs in CD14+ cells. They were mostly hypermethylated in RRMS relapse in both cell populations. However, the proportion of hypermethylated DMPs (as well as DMPs located within or in close proximity to CpG islands) was significantly higher in CD4+ T lymphocytes. In CD4+ and CD14+ cells we identified 469 and 67 DMP-containing genes, respectively; 25 of them were common for two cell populations. When we conducted a search for differentially methylated genomic regions (DMRs), we found a CD4+ specific DMR hypermethylated in RRMS relapse (adj. p = 0.03) within the imprinted GNAS locus. Total level of the protein-coding GNAS transcripts in CD4+ T cells decreased significantly in the row from healthy control to RRMS remission and then to RRMS relapse (adj. p = 3.1 × 10 and 0.011, respectively).
Our findings suggest that the epigenetic mechanism of DNA methylation in immune cells contributes to the development of RRMS relapse. Further studies are now required to validate these results and shed light on the molecular mechanisms underlying the observed GNAS methylation and expression changes.
复发缓解型多发性硬化症（RRMS）是多发性硬化症最常见的形式，其特征是神经恶化期后伴有临床缓解期。RRMS 复发是由中枢神经系统任何部位的急性自身免疫炎症过程引起的。尽管目前尚无法准确预测病情恶化的发生，但已知各种外部因素会影响其风险。这些因素可能通过基因表达调控的表观遗传机制触发病理过程，首先是通过 DNA 甲基化的变化。
在本研究中，我们首次分析了 RRMS 患者在复发和缓解期的 CD4+T 淋巴细胞和 CD14+单核细胞中全基因组 DNA 甲基化模式。使用 qPCR 研究了差异甲基化对基因表达的影响。
我们在 CD4+细胞中发现了 743 个差异甲基化 CpG 位置（DMPs），而在 CD14+细胞中仅发现了 113 个 DMPs。在这两个细胞群体中，它们在 RRMS 复发时大多呈高甲基化状态。然而，在 CD4+T 淋巴细胞中，高甲基化 DMPs 的比例（以及位于 CpG 岛内部或附近的 DMPs）显著更高。在 CD4+和 CD14+细胞中，我们分别鉴定了 469 个和 67 个含有 DMP 的基因，其中 25 个是两种细胞群体共有的。当我们进行差异甲基化基因组区域（DMR）搜索时，我们在 RRMS 复发时发现了一个位于印迹 GNAS 基因座内的 CD4+特异性 DMR 呈高甲基化状态（adj. p = 0.03）。在从健康对照组到 RRMS 缓解期再到 RRMS 复发的过程中，CD4+T 细胞中蛋白编码 GNAS 转录物的总水平显著降低（adj. p = 3.1×10 和 0.011，分别）。
我们的研究结果表明，免疫细胞中的 DNA 甲基化表观遗传机制有助于 RRMS 复发的发生。目前需要进一步的研究来验证这些结果，并阐明观察到的 GNAS 甲基化和表达变化的分子机制。
