Integrated long non-coding RNA analyses identify novel regulators of epithelial-mesenchymal transition in the mouse model of pulmonary fibrosis.
Integrated long non-coding RNA analyses identify novel regulators of epithelial-mesenchymal transition in the mouse model of pulmonary fibrosis.
复制标题
整合的长非编码 RNA 分析确定了小鼠肺纤维化模型中上皮-间质转化的新型调节因子。
DOI：
10.1111/jcmm.12783
复制
发表时间：
2016-07
影响因子：
5.3
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Sun H;Chen J;Qian W;Kang J;Wang J;Jiang L;Qiao L;Chen W;Zhang J
特发性肺纤维化(IPF)是一种以成纤维细胞异常聚集和细胞外基质沉积为特征的慢性致死性肺部疾病。越来越多的证据支持肺泡上皮细胞上皮-间充质转化(EMT)是IPF发病机制中的关键过程。尽管博莱霉素诱导急性肺损伤是目前研究最多的肺纤维化动物模型，但人们仍有兴趣寻找其他模型来了解其共同和/或特定的病理机制。在这项研究中，我们通过腹腔注射百草枯建立了小鼠肺损伤和进行性间质纤维化的模型，百草枯是一种广泛使用的除草剂，已知会导致人类肺纤维化。利用转录组测序和芯片分析，我们对百草枯诱导的肺纤维化组织中长非编码RNA(LncRNAs)的表达进行了分析，发现513个上调的LncRNAs和204个下调的LncRNAs。基因本体论分析表明，差异表达的lncRNAs参与了细胞分化、上皮形态发生和伤口愈合等与EMT密切相关的通路。此外，我们还鉴定了两个上调表达的lncRNAs UC.77和2700086A05Rik在进化上保守的靶基因分别为ZEB2和Hoxa3，这两个基因都是EMT的重要调节因子。UC.77或2700086A05Rik在人肺上皮细胞中过表达可诱导EMT，表现为各种EMT标志物的基因和蛋白表达及细胞形态的变化。总之，我们的结果揭示了lncRNA在肺纤维化过程中对EMT的调节中的关键作用，并为发现新的IPF分子标志物和治疗靶点提供了潜在的途径。
Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease characterized by aberrant accumulation of fibroblast population and deposition of extra cellular matrix. Increasing evidence support that epithelial‐mesenchymal transition (EMT) of alveolar epithelial cells is a critical process in the pathogenesis of IPF. Although delivery of bleomycin to induce acute lung injury is the most well‐studied animal model of pulmonary fibrosis, there is considerable interest to pursue other models to understand the common and/or specific pathological mechanisms. In this study, we established a mouse model of pulmonary injury and progressive interstitial fibrosis via intraperitoneal injection of paraquat, a widely used herbicide known to cause pulmonary fibrosis in human. Using transcriptome sequencing and microarray analysis, we profiled expression of long non‐coding RNAs (lncRNAs) and identified 513 up‐regulated and 204 down‐regulated lncRNAs in paraquat‐induced fibrotic lung tissues. Gene ontology analysis revealed that the differentially expressed lncRNAs are implicated in cell differentiation, epithelium morphogenesis and wound healing, pathways closely associated with EMT. Furthermore, we identified the evolutionally conserved target genes of two up‐regulated lncRNAs, uc.77 and 2700086A05Rik, as Zeb2 and Hoxa3, respectively, both of which are important modulators of EMT. Consistently, overexpression of uc.77 or 2700086A05Rik in human lung epithelial cells induced EMT as demonstrated by changes in gene and protein expression of various EMT markers and cell morphology. Collectively, our results uncovered a crucial role of lncRNA in the regulation of EMT during lung fibrosis and provide potential avenues for the discovery of novel molecular markers and therapeutic targets for IPF.