Nottingham NIHR Biomedical Research Centre, Nottingham MRC Molecular Pathology Node, Division of Respiratory Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham, UK.
BC Children's Hospital Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Clin Epigenetics. 2020 Oct 2;12(1):145. doi: 10.1186/s13148-020-00931-4.
Mesenchymal fibroblasts are ubiquitous cells that maintain the extracellular matrix of organs. Within the lung, airway and parenchymal fibroblasts are crucial for lung development and are altered with disease, but it has been difficult to understand their roles due to the lack of distinct molecular markers. We studied genome-wide DNA methylation and gene expression in airway and parenchymal lung fibroblasts from healthy and asthmatic donors, to identify a robust cell marker and to determine if these cells are molecularly distinct in asthma.
Airway (N = 8) and parenchymal (N = 15) lung fibroblasts from healthy individuals differed in the expression of 158 genes, and DNA methylation of 3936 CpGs (Bonferroni adjusted p value < 0.05). Differential DNA methylation between cell types was associated with differential expression of 42 genes, but no single DNA methylation CpG feature (location, effect size, number) defined the interaction. Replication of gene expression and DNA methylation in a second cohort identified TWIST1 gene expression, DNA methylation and protein expression as a cell marker of airway and parenchymal lung fibroblasts, with DNA methylation having 100% predictive discriminatory power. DNA methylation was differentially altered in parenchymal (112 regions) and airway fibroblasts (17 regions) with asthmatic status, with no overlap between regions.
Differential methylation of TWIST1 is a robust cell marker of airway and parenchymal lung fibroblasts. Airway and parenchymal fibroblast DNA methylation are differentially altered in individuals with asthma, and the role of both cell types should be considered in the pathogenesis of asthma.
间充质成纤维细胞是普遍存在的细胞，它们维持着器官的细胞外基质。在肺部，气道和成纤维细胞对于肺的发育至关重要，并且在疾病状态下会发生改变，但由于缺乏独特的分子标志物，因此很难了解它们的作用。我们研究了来自健康和哮喘供体的气道和成纤维细胞的全基因组 DNA 甲基化和基因表达，以确定一个稳健的细胞标志物，并确定这些细胞在哮喘中是否具有分子上的差异。
来自健康个体的气道（N = 8）和成纤维细胞（N = 15）在 158 个基因的表达和 3936 个 CpG 的 DNA 甲基化（Bonferroni 调整的 p 值<0.05）上存在差异。细胞类型之间的差异 DNA 甲基化与 42 个基因的差异表达相关，但没有单个 DNA 甲基化 CpG 特征（位置、效应大小、数量）定义了这种相互作用。在第二个队列中对基因表达和 DNA 甲基化的复制鉴定出 TWIST1 基因表达、DNA 甲基化和蛋白表达作为气道和成纤维细胞的细胞标志物，其中 DNA 甲基化具有 100%的预测区分能力。在哮喘患者中，成纤维细胞（112 个区域）和气道成纤维细胞（17 个区域）的 DNA 甲基化存在差异，且区域之间没有重叠。
TWIST1 的差异甲基化是气道和成纤维细胞的一个稳健的细胞标志物。哮喘患者的气道和肺成纤维细胞的 DNA 甲基化存在差异，两种细胞类型的作用都应该在哮喘的发病机制中得到考虑。
