Multitranscriptome analyses reveal prioritized genes specifically associated with liver fibrosis progression independent of etiology
Multitranscriptome analyses reveal prioritized genes specifically associated with liver fibrosis progression independent of etiology
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多转录组分析揭示了与肝纤维化进展特异性相关的优先基因，与病因无关
DOI：
10.1152/ajpgi.00339.2018
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发表时间：
2019-06-01
影响因子：
4.5
通讯作者：
You, Hong
中科院分区：
文献类型：
--
作者：
Chen, Wei;Wu, Xiaoning;You, Hong
消除或抑制致病因素可提高肝纤维化消退的可能性。然而，不同的损伤性刺激会导致不同病因的纤维化，这反过来又可能阻碍肝纤维化特异性治疗药物的发现。因此，各种病因引起的肝纤维化所共有的类似细胞和分子事件应该得到澄清。我们目前的研究系统地整合了基因表达综合数据库中关于不同病因的肝纤维化的五个公开可用的转录组数据集，并进行了一系列的生物信息学分析和实验验证。共有111个显著上调的基因和16个显著下调的基因被鉴定为肝纤维化特异性基因，与任何病因无关。这些基因主要富集在一些京都基因和基因组百科全书通路中，包括“PI3K-AKT信号通路”、“局灶黏着”和“ecm受体相互作用”。随后，筛选了5个肝纤维化特异性优先基因，包括COL4A2、THBS2、ITGAV、LAMB1和PDGFRA。这些基因相互之间与肝纤维化进展呈正相关。此外，当它们被视为应用于主成分分析图的观察变量时，它们可以在具有不同病因的训练和验证数据集中稳健地分离样品的所有阶段。激活的小鼠肝星状细胞（hsc）和转化生长因子β 1处理的LX-2细胞证实了这五个基因的表达。此外，THBS2蛋白在肝纤维化啮齿动物模型中表达增强，可促进HSC活化和增殖，促进NOTCH1/JAG1在HSC中的表达。总的来说，我们目前的研究可能为肝纤维化治疗提供潜在的靶点，并有助于更深入地了解肝纤维化的分子基础。新的和值得注意的优先肝纤维化特异性基因THBS2， COL4A2， ITGAV， LAMB1和PDGFRA被确定并与肝纤维化进展显著相关，并且可以联合区分肝纤维化分期，无论任何病因。在确定的肝纤维化特异性优先靶点中，THBS2蛋白在肝纤维化啮齿动物模型中被证实增强，其可促进肝星状细胞（hepatic stellate cell， HSC）的活化和增殖，促进NOTCH1/JAG1在HSC中的表达。
Elimination or suppression of causative factors can raise the possibility of liver fibrosis regression. However, different injurious stimuli will give fibrosis from somewhat different etiologies, which, in turn, may hamper the discovery of liver fibrosis-specific therapeutic drugs. Therefore, the analogical cellular and molecular events shared by various etiologyevoked liver fibrosis should be clarified. Our present study systematically integrated five publicly available transcriptomic data sets regarding liver fibrosis with different etiologies from the Gene Expression Omnibus database and performed a series of bioinformatics analyses and experimental verifications. A total of 111 significantly upregulated and 16 downregulated genes were identified specific to liver fibrosis independent of any etiology. These genes were predominately enriched in some Kyoto Encyclopedia of Genes and Genomes pathways, including the "PI3K-AKT signaling pathway," "Focal adhesion," and "ECM-receptor interaction." Subsequently, five prioritized liver fibrosis-specific genes, including COL4A2, THBS2, ITGAV, LAMB1, and PDGFRA, were screened. These genes were positively associated with each other and liver fibrosis progression. In addition, they could robustly separate all stages of samples in both training and validation data sets with diverse etiologies when they were regarded as observed variables applied to principal component analysis plots. Expressions of all five genes were confirmed in activated primary mouse hepatic stellate cells (HSCs) and transforming growth factor beta 1-treated LX-2 cells. Moreover, THBS2 protein was enhanced in liver fibrosis rodent models, which could promote HSC activation and proliferation and facilitate NOTCH1/JAG1 expression in HSCs. Overall, our current study may provide potential targets for liver fibrosis therapy and aid to a deeper understanding of the molecular underpinnings of liver fibrosis.NEW & NOTEWORTHY Prioritized liver fibrosis-specific genes THBS2, COL4A2, ITGAV, LAMB1, and PDGFRA were identified and significantly associated with liver fibrosis progression and could be combined to discriminate liver fibrosis stages regardless of any etiology. Among the identified prioritized liver fibrosis-specific targets, THBS2 protein was confirmed to be enhanced in liver fibrosis rodent models, which could promote hepatic stellate cell (HSC) activation and proliferation and facilitate NOTCH1/JAG1 expression in HSCs.