Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation
Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation
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DOI：
10.1172/jci122106
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发表时间：
2019-05-01
影响因子：
15.9
通讯作者：
Blackburn, Michael R.
中科院分区：
文献类型：
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作者：
Weng, Tingting;Ko, Junsuk;Blackburn, Michael R.
特发性肺纤维化（IPF）是一种预后差且治疗选择少的致命疾病。细胞外基质（ECM）的病理性重塑是驱动疾病发病机制的关键因素，尽管其潜在机制仍不清楚。最近已证明，选择性多聚腺苷酸化（阿帕）通过改变miRNA敏感性驱动纤维化因子的表达，在细胞应激反应中发挥重要作用，但尚未确定与IPF的联系。在这里，我们证明了CFIm 25，一个阿帕的全局调节因子，在IPF患者和肺纤维化小鼠的肺中下调，其表达在α-平滑肌肌动蛋白阳性（α-SMA阳性）成纤维细胞中选择性降低。在健康人肺成纤维细胞中敲低CFIm 25后，我们鉴定了808个具有缩短的3 '-UTR的基因，包括参与TGF-β信号传导途径、Wnt信号传导途径和癌症途径的基因。关键促纤维化因子的表达被IPF成纤维细胞中的CFIm 25过表达抑制。最后，我们证明了使用Col 1a 1或Foxd 1启动子删除成纤维细胞或肌成纤维细胞前体中的CFIm 25增强博莱霉素暴露后的肺纤维化。总的来说，我们的研究结果确定CFIm 25下调是肺纤维化中促纤维化基因表达升高的重要机制。
Idiopathic pulmonary fibrosis (IPF) is a deadly disease with a poor prognosis and few treatment options. Pathological remodeling of the extracellular matrix (ECM) is a key factor that drives the disease pathogenesis, although the underlying mechanisms remain unknown. Alternative polyadenylation (APA) has recently been shown to play a major role in cellular responses to stress by driving the expression of fibrotic factors through the alteration of miRNA sensitivity, but a connection to IPF has not been established. Here, we demonstrated that CFIm25, a global regulator of APA, was downregulated in the lungs of patients with IPF and mice with pulmonary fibrosis, with its expression selectively reduced in alpha-smooth muscle actin-positive (alpha-SMA-positive) fibroblasts. Following CFIm25 knockdown in healthy human lung fibroblasts, we identified 808 genes with shortened 3'-UTRs, including those involved in the TGF-beta signaling pathway, the Wnt signaling pathway, and cancer pathways. The expression of key profibrotic factors was suppressed by CFIm25 overexpression in IPF fibroblasts. Finally, we demonstrated that deletion of CFIm25 in fibroblasts or myofibroblast precursors using either the Col1a1 or the Foxd1 promoter enhanced pulmonary fibrosis after bleomycin exposure. Collectively, our results identified CFIm25 downregulation as an important mechanism for elevating profibrotic gene expression in pulmonary fibrosis.