Identification of Key Transcription Factors AP-1 and AP-1-Dependent miRNAs Forming a Co-Regulatory Network Controlling PTEN in Liver Ischemia/Reperfusion Injury

Abstract

Liver ischemia/reperfusion (I/R) injury is a complex and common clinical disease with limited therapeutic options. The aim of our study was to discover the candidate target genes in liver I/R injury and to further elucidate the potential regulatory mechanisms, especially the ones involving transcription factors and miRNAs. The analysis of mouse data set GSE10657 from Gene Expression Omnibus database (GEO) revealed 203 differentially expressed genes (DEGs) including 19 transcription factors (TFs). Functional and pathway enrichment analyses were conducted to explore their biological functions. We further obtained the targets of TFs and miRNAs, to form our TF-mRNA/TF-miRNA-mRNA co-regulatory network. In our network, we found that the important subunits of activator protein 1 (AP-1) including JUN, FOS and ATF3, were hub genes in liver I/R injury. AP-1 target genes were activated in our mouse models. AP-1 could transcriptionally activate phosphatase and tensin homolog (PTEN) while AP-1-dependent miRNAs countered this effect. In conclusion, this study suggested that AP-1, together with AP-1-dependent miRNAs formed a co-regulatory network enabling AP-1 target genes to be tightly controlled, which will complete the mechanism of liver ischemia/reperfusion injury and provide direction for finding potential therapeutic targets.