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.

中文翻译：

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TWIST1 DNA 甲基化是哮喘中差异甲基化的气道和肺实质成纤维细胞的细胞标志物

间充质成纤维细胞是维持器官细胞外基质的普遍存在的细胞。在肺内，气道和实质成纤维细胞对肺发育至关重要，并且会随着疾病而改变，但由于缺乏不同的分子标记，很难理解它们的作用。我们研究了来自健康和哮喘供体的气道和肺实质成纤维细胞中的全基因组 DNA 甲基化和基因表达，以确定强大的细胞标记物并确定这些细胞在哮喘中是否具有分子差异。来自健康个体的气道 (N = 8) 和肺实质 (N = 15) 肺成纤维细胞在 158 个基因的表达和 3936 个 CpG 的 DNA 甲基化方面存在差异（Bonferroni 调整后的 p 值 < 0.05）。细胞类型之间的差异 DNA 甲基化与 42 个基因的差异表达有关，但没有单一的 DNA 甲基化 CpG 特征（位置、效应大小、数量）定义了相互作用。在第二个队列中基因表达和 DNA 甲基化的复制将 TWIST1 基因表达、DNA 甲基化和蛋白质表达确定为气道和肺实质成纤维细胞的细胞标志物，其中 DNA 甲基化具有 100% 的预测辨别力。哮喘状态的实质（112 个区域）和气道成纤维细胞（17 个区域）的 DNA 甲基化发生差异性改变，区域之间没有重叠。TWIST1 的差异甲基化是气道和肺实质成纤维细胞的强大细胞标志物。哮喘患者的气道和实质成纤维细胞 DNA 甲基化发生差异性改变，应考虑这两种细胞类型在哮喘发病机制中的作用。