Transcriptional regulatory model of fibrosis progression in the human lung
Transcriptional regulatory model of fibrosis progression in the human lung
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DOI：
10.1172/jci.insight.131597
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发表时间：
2019-11-14
期刊：
影响因子：
8
通讯作者：
Kaminski, Naftali
中科院分区：
文献类型：
--
作者：
McDonough, John E.;Ahangari, Farida;Kaminski, Naftali
为了建立人类肺部纤维化进展的系统生物学模型，我们对来自10例特发性肺纤维化（IPF）和6例对照肺的95个样本进行了RNA测序和microRNA分析。通过显微ct测量肺泡表面密度（ASD）评估每个样本的纤维化程度，并通过组织学证实。使用线性混合效应模型和动态调控事件挖掘（DREM）来识别调控基因表达网络。差异基因表达分析发现，一组核心基因在纤维化前增加或减少，组织学上明显，随着晚期纤维化继续改变。OREM生成了一个系统生物学模型（www.sb.cs.cmu.edu/IPFReg），该模型确定了具有特异性调节轻度或晚期纤维化的microrna和转录因子的逐渐分化的基因表达轨迹。我们通过证明POU2AF1的表达（之前与肺纤维化无关，但被模型提出作为调节因子）在IPF肺的B淋巴细胞中增加来证实模型预测，并且POU2AF1敲除小鼠免受博莱霉素诱导的肺纤维化的影响。我们的研究结果揭示了与中度或晚期纤维化相比，在结构正常的IPF组织中基因表达变化的独特调节，并提示了每个阶段不同的调节机制。
To develop a systems biology model of fibrosis progression within the human lung we performed RNA sequencing and microRNA analysis on 95 samples obtained from 10 idiopathic pulmonary fibrosis (IPF) and 6 control lungs. Extent of fibrosis in each sample was assessed by microCT-measured alveolar surface density {ASD) and confirmed by histology. Regulatory gene expression networks were identified using linear mixed-effect models and dynamic regulatory events miner (DREM). Differential gene expression analysis identified a core set of genes increased or decreased before fibrosis was histologically evident that continued to change with advanced fibrosis. OREM generated a systems biology model (www.sb.cs.cmu.edu/IPFReg) that identified progressively divergent gene expression tracks with microRNAs and transcription factors that specifically regulate mild or advanced fibrosis. We confirmed model predictions by demonstrating that expression of POU2AF1, previously unassociated with lung fibrosis but proposed by the model as regulator, is increased in B lymphocytes in IPF lungs and that POU2AF1-knockout mice were protected from bleomycin-induced lung fibrosis. Our results reveal distinct regulation of gene expression changes in IPF tissue that remained structurally normal compared with moderate or advanced fibrosis and suggest distinct regulatory mechanisms for each stage.