CD4+ T 淋巴细胞和 CD14+ 单核细胞中不同的全基因组 DNA 甲基化模式是多发性硬化复发和缓解的特征：聚焦 GNAS。

IF 2.9 3区医学 Q2 CLINICAL NEUROLOGY

Multiple sclerosis and related disorders Pub Date : 2024-09-29 DOI:10.1016/j.msard.2024.105910

Ivan Kiselev , Olga Kulakova , Olga Baturina , Marsel Kabilov , Alexey Boyko , Olga Favorova

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引用次数: 0

摘要

背景：复发缓解型多发性硬化症（RRMS）是多发性硬化症中最常见的一种，患者的神经系统症状会在一段时间恶化后随之出现临床缓解。RRMS 复发是由急性自身免疫性炎症过程引起的，可发生在中枢神经系统的任何部位。虽然目前还无法准确预测病情恶化的发展，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（首先是通过 DNA 甲基化的变化）触发病理过程：在本研究中，我们首次分析了同一复发和缓解期 RRMS 患者 CD4+ T 淋巴细胞和 CD14+ 单核细胞的全基因组 DNA 甲基化模式。我们使用 qPCR 研究了不同甲基化对基因表达的影响：结果：我们在 CD4+ 细胞中发现了 743 个差异甲基化 CpG 位点（DMPs），而在 CD14+ 细胞中仅发现了 113 个 DMPs。在RRMS复发时，这两种细胞群中大部分都存在高甲基化。然而，CD4+ T 淋巴细胞中高甲基化的 DMPs（以及位于 CpG 岛内或靠近 CpG 岛的 DMPs）比例明显更高。在 CD4+ 细胞和 CD14+ 细胞中，我们分别发现了 469 个和 67 个含 DMP 的基因；其中 25 个基因是两个细胞群共有的。当我们搜索差异甲基化基因组区域（DMRs）时，我们发现在RRMS复发中，CD4+特异性DMR在印记GNAS基因座内发生了高甲基化（adj. p = 0.03）。在从健康对照到RRMS缓解再到RRMS复发的过程中，CD4+T细胞中编码蛋白质的GNAS转录物总水平显著下降（adj. p = 3.1 × 10-7 and 0.011, respectively）：我们的研究结果表明，免疫细胞中DNA甲基化的表观遗传学机制导致了RRMS的复发。现在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。

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Different genome-wide DNA methylation patterns in CD4+ T lymphocytes and CD14+ monocytes characterize relapse and remission of multiple sclerosis: Focus on GNAS

Background

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.

Methods

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.

Results

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^–7 and 0.011, respectively).

Conclusion

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.

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来源期刊

Multiple sclerosis and related disorders CLINICAL NEUROLOGY-

CiteScore

5.80

自引率

20.00%

发文量

814

审稿时长

66 days

期刊介绍： Multiple Sclerosis is an area of ever expanding research and escalating publications. Multiple Sclerosis and Related Disorders is a wide ranging international journal supported by key researchers from all neuroscience domains that focus on MS and associated disease of the central nervous system. The primary aim of this new journal is the rapid publication of high quality original research in the field. Important secondary aims will be timely updates and editorials on important scientific and clinical care advances, controversies in the field, and invited opinion articles from current thought leaders on topical issues. One section of the journal will focus on teaching, written to enhance the practice of community and academic neurologists involved in the care of MS patients. Summaries of key articles written for a lay audience will be provided as an on-line resource. A team of four chief editors is supported by leading section editors who will commission and appraise original and review articles concerning: clinical neurology, neuroimaging, neuropathology, neuroepidemiology, therapeutics, genetics / transcriptomics, experimental models, neuroimmunology, biomarkers, neuropsychology, neurorehabilitation, measurement scales, teaching, neuroethics and lay communication.