目的:小鼠通常用作药物性肝损伤(DILI)的动物模型,然而,小鼠和人类之间的发病机制存在显着差异。这项研究旨在比较人和小鼠在对乙酰氨基酚(APAP)诱导的肝损伤(AILI)中的基因表达。并研究了两个物种之间生物学过程的异同。
方法:从GEO获得的一对公共数据集(GSE218879和GSE120652)使用R语言的“Limma”软件包进行分析,并鉴定了差异表达基因(DEGs),包括共表达的DEGs(co-DEGs)和特异性表达的DEGs(specific-DEGs)。基因集富集分析(GSEA),基因本体论(GO)和京都基因和基因组百科全书(KEGG)对特异性DEG和共DEG进行分析。co-DEG也用于构建转录因子(TF)-基因网络,用于分析集线器基因的基因-miRNA相互作用网络和蛋白质-蛋白质相互作用(PPI)网络。
结果:小鼠样本包含1052个上调基因和1064个下调基因,而人类样本包含1156个上调基因和1557个下调基因。在获取DEG之间的交叉点之后,仅鉴定出154个共同下调的DEG和89个共同上调的DEG,比例低于10%。提示在药物性肝损伤中,小鼠和人类之间的基因表达存在显着差异。小鼠特异性DEGs主要参与与细胞凋亡和内质网应激相关的过程,而人类特异性DEGs集中在分解代谢过程中。对共调节基因的分析表明,它们主要富集在生物合成和代谢相关过程中。然后从co-DEG构建了一个包含189个节点和380个边缘的PPI网络,并通过Mcode获得了两个模块。我们通过三种度算法筛选出10个hub基因,MCC和MNC,包括CYP7A1,LSS,SREBF1,FASN,CD44,SPP1,ITGAV,ANXA5、LGALS3和PDGFRA。此外,TFs,如FOXC1、HINFP、NFKB1,miRNAs如mir-744-5p,mir-335-5p,mir-149-3p,mir-218-5p,mir-10a-5p可能是hub基因的关键调控因子。
结论:比较了AILI小鼠模型和患者的DEG,并确定了常见的生物过程。通过一系列生物信息学分析,确定了小鼠和人之间共表达的信号通路和hub基因,这可能对揭示AILI的分子机制更有价值。
OBJECTIVE: Mice are routinely utilized as animal models of drug-induced liver injury (DILI), however, there are significant differences in the pathogenesis between mice and humans. This study aimed to compare gene expression between humans and mice in acetaminophen (APAP)-induced liver injury (AILI), and investigate the similarities and differences in biological processes between the two species.
METHODS: A pair of public datasets (GSE218879 and GSE120652) obtained from GEO were analyzed using \"Limma\" package in R language, and differentially expressed genes (DEGs) were identified, including co-expressed DEGs (co-DEGs) and specific-expressed DEGS (specific-DEGs). Analysis of Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed analyses for specific-DEGs and co-DEGs. The co-DEGs were also used to construct transcription factor (TF)-gene network, gene-miRNA interactions network and protein-protein interaction (PPI) network for analyzing hub genes.
RESULTS: Mouse samples contained 1052 up-regulated genes and 1064 down-regulated genes, while human samples contained 1156 up-regulated genes and 1557 down-regulated genes. After taking the intersection between the DEGs, only 154 co-down-regulated and 89 co-up-regulated DEGs were identified, with a proportion of less than 10%. It was suggested that significant differences in gene expression between mice and humans in drug-induced liver injury. Mouse-specific-DEGs predominantly engaged in processes related to apoptosis and endoplasmic reticulum stress, while human-specific-DEGs were concentrated around catabolic process. Analysis of co-regulated genes reveals showed that they were mainly enriched in biosynthetic and metabolism-related processes. Then a PPI network which contains 189 nodes and 380 edges was constructed from the co-DEGs and two modules were obtained by Mcode. We screened out 10 hub genes by three algorithms of Degree, MCC and MNC, including CYP7A1, LSS, SREBF1, FASN, CD44, SPP1, ITGAV, ANXA5, LGALS3 and PDGFRA. Besides, TFs such as FOXC1, HINFP, NFKB1, miRNAs like mir-744-5p, mir-335-5p, mir-149-3p, mir-218-5p, mir-10a-5p may be the key regulatory factors of hub genes.
CONCLUSIONS: The DEGs of AILI mice models and those of patients were compared, and common biological processes were identified. The signaling pathways and hub genes in co-expression were identified between mice and humans through a series of bioinformatics analyses, which may be more valuable to reveal molecular mechanisms of AILI.