Genomic Responses of Mouse Synovial Fibroblasts During Tumor Necrosis Factor-Driven Arthritogenesis Greatly Mimic Those in Human Rheumatoid Arthritis
Genomic Responses of Mouse Synovial Fibroblasts During Tumor Necrosis Factor-Driven Arthritogenesis Greatly Mimic Those in Human Rheumatoid Arthritis
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DOI：
10.1002/art.40128
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发表时间：
2017-08-01
影响因子：
13.3
通讯作者：
Kollias, George
中科院分区：
文献类型：
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作者：
Ntougkos, Evangelos;Chouvardas, Panagiotis;Kollias, George
客观的。滑膜成纤维细胞的异常激活是类风湿性关节炎（RA）发病机制的关键决定因素。本研究的目的是绘制人类肿瘤坏死因子 (TNF) 转基因关节炎模型疾病进展过程中该细胞类型发生的基因表达和表观遗传变化图谱，并确定与人类滑膜成纤维细胞的共性。方法。我们使用深度测序来探测培养的小鼠关节炎滑膜成纤维细胞在疾病的 3 个阶段以及用人 TNF 刺激的滑膜成纤维细胞的转录组、甲基化组和染色质景观。我们在基因、通路和网络水平上进行了生物信息学分析，比较了小鼠和人类的数据，并验证了两个物种中选定的基因。结果。我们发现滑膜成纤维细胞关节炎性反映在转录失调的独特动态模式中，这种失调在先天免疫反应和间充质分化途径中尤其丰富。这些变化的功能代表性子集与甲基化相关，主要是在基因体中。关节炎发生状态涉及高活性启动子，其以组蛋白 H3K4 三甲基化为标志。小鼠和人类数据在失调基因水平上存在显着重叠，在更大程度上在通路水平上存在显着重叠。结论。这项研究是对小鼠滑膜成纤维细胞在进行性 TNF 驱动的关节炎发生过程中发生的致病变化的首次系统检查。与相应的人类RA滑膜成纤维细胞数据的显着相关性进一步验证了人类TNF转基因小鼠作为人类疾病的可靠模型。这项工作中生成的数据资源可以作为发现新的致病机制和疾病生物标志物的框架。
Objective. Aberrant activation of synovial fibroblasts is a key determinant in the pathogenesis of rheumatoid arthritis (RA). The aims of this study were to produce a map of gene expression and epigenetic changes occurring in this cell type during disease progression in the human tumor necrosis factor (TNF)transgenic model of arthritis and to identify commonalities with human synovial fibroblasts.Methods. We used deep sequencing to probe the transcriptome, the methylome, and the chromatin landscape of cultured mouse arthritogenic synovial fibroblasts at 3 stages of disease, as well as synovial fibroblasts stimulated with human TNF. We performed bioinformatics analyses at the gene, pathway, and network levels, compared mouse and human data, and validated selected genes in both species.Results. We found that synovial fibroblast arthritogenicity was reflected in distinct dynamic patterns of transcriptional dysregulation, which was especially enriched in pathways of the innate immune response and mesenchymal differentiation. A functionally representative subset of these changes was associated with methylation, mostly in gene bodies. The arthritogenic state involved highly active promoters, which were marked by histone H3K4 trimethylation. There was significant overlap between the mouse and human data at the level of dysregulated genes and to an even greater extent at the level of pathways.Conclusion. This study is the first systematic examination of the pathogenic changes that occur in mouse synovial fibroblasts during progressive TNF-driven arthritogenesis. Significant correlations with the respective human RA synovial fibroblast data further validate the human TNF- transgenic mouse as a reliable model of the human disease. The resource of data generated in this work may serve as a framework for the discovery of novel pathogenic mechanisms and disease biomarkers.