DNA methylation in the development of multiple sclerosis

摘要 该应用涉及影响多发性硬化症(MS)风险的表观遗传学事件的研究 和进步。我们给出了与广泛差异一致的初步结果。 诊断时外周CD19 B细胞中的低甲基化，提供了一种与 抗CD20抗体治疗本病的临床疗效。我们在这些结果的基础上 获得信息丰富和多样化的数据和样本集，以便在具体目标1中同时提出 单细胞基因表达(scRNA-seq)、染色质可及性(scATAC-seq)的评估 脑脊液和外周血单核细胞表面标志物的检测 在临床发病时治疗幼稚的多发性硬化症患者和匹配良好的对照组，并在目标2至 个体的DNA变异导致全球和细胞特有的遗传负担与 疾病表现。在目标3中，我们将新出现的表观遗传学和转录组特征与 使用Beacon®系统光流控平台可视化和评估细胞表型 在单细胞水平上。在目标4中，我们实现了一种有针对性的三峰单细胞分析来描述 主要MS易感基因座，主要组织相容性复合体的表观遗传景观 染色体6p21。通过系统地整合单细胞染色质状态、DNA变异和基因 表达数据，我们期望获得关于发病机制的重要新信息。此外，我们还将 确定与多发性硬化症临床发病相关的细胞特异性表观遗传学特征，可能作为 做作状态的生物标志物。研究参与者的细致临床随访提供了一种 有机会评估他们的预后潜力。

Summary This application is concerned with the study of epigenetics events affecting multiple sclerosis (MS) risk and progression. We present preliminary results consistent with widespread differential hypomethylation in peripheral CD19+ B cells at the time of diagnosis, posing a mechanistic link to the clinical efficiency of anti-CD20 antibody treatment for this disease. We build on these results and access to informative and diverse data- and sample-sets to propose in Specific Aim 1 the simultaneous assessment of single-cell gene expression (scRNA-seq), chromatin accessibility (scATAC-seq), and cell surface markers in paired cerebrospinal fluid (CSF) and peripheral blood mononuclear cells from treatment naïve MS patients at the time of clinical onset and well matched controls, and link in Aim 2 to the individuals’ DNA variance to develop global and cell-specific genetic burdens associated with disease expression. In Aim 3 we connect the emerging epigenetic and transcriptome signatures with cell function using the Beacon® system optofluidic platform to visualize and assess cellular phenotypes at the single-cell level. In Aim 4 we implement a targeted trimodal single-cell assay to describe the epigenetic landscape of the principal MS susceptibility locus, the Major Histocompatibility Complex in chromosome 6p21. By systematically integrating single cell chromatin states, DNA variance, and gene expression data, we expect to gain important novel information about pathogenesis. Moreover, we will identify cell-specific epigenetic signatures associated with MS clinical onset, potentially serving as biomarkers of affectation status. The meticulous clinical follow up of study participants offers an opportunity to assess their prognostic potential.