Identification And Analysis Of Hub Transcriptional Factors Related To Acetaminophen-induced Liver Injury

Objective:Acetaminophen-induced liver injury(AILI)is one of the most common causes of acute liver failure,and its pathogenesis remains unclear and there is a lack of effective early diagnostic markers.Methods:We searched three TF online databases including the Catalog of Inferred Sequence Binding Preferences(CIS-BP),Human Transcription Factor Database(Human TFDB),and Human Transcription Factor.The intersections of the TFs downloaded from these three databases were included in the research.AILI-related datasets were retrieved in the GEO databases.The differential expressions of genes(DEGs)between experimental group and control group were analyzed using R.DEGs were intersected with the TFs downloaded from the three databases to obtain the AILI-related DETFs.The molecular mechanism of AILI was revealed by enrichment analysis and protein-protein interaction(PPI)networks.The expressions of hub TFs in the early stages of AILI was validated using rank sum test.Finally,the p ROC package was used to evaluate the sensitivity and specificity of these hub TFs in the diagnosis of early-stage AILI.Results:We downloaded 1639 TFs from CIS-BP,1665 from Human TFDB,and 1639 from Human Transcription Factor.The three TFs databases were intersected,which yielded a total of 1507 TFs.Two relevant data sets,GSE53216 and GSE51952 were obtained.For the GSE53216 dataset,10 m M of APAP induces AILI at 12hour、24 hour、48 hour、72hour.506、633、816、983 up-regulated DEGs were selected from the GSE53216,411、556、586、643 down-regulated DEGs were selected.858 DEGs showed a persistent increase as acute liver injury progressed.949 DEGs had a persistent decrease as acute liver injury progressed.Intersection of these 1507 TFs with 1807 AILI-related up-regulated and down-regulated DEGs yielded 97 AILI-related DETFs(41 up-regulated and 56 down-regulated).97 AILI-related DETFs were mainly enriched at regions associated with transcriptional activity,rhythmic process,cell fate commitment,liver development,and hepaticobiliary system development.Ten hub TFs(MYC,TP53,CEBPB,FOXM1,E2F1,EGR2,FOSL1,JUND,E2F7 and E2F8)were obtained from the PPI networks.In the early stage of AILI,the expressions of MYC,TP53,CEBPB,E2F1,JUND,and E2F7 significantly changed compared with the control group,and these hub TFs had high sensitivity and specificity;in contrast,the expressions of FOXM1,EGR2,FOSL1 and E2F8 were not significantly different from those in the control group,and these hub TFs had certain sensitivity and specificity.Conclusion:Ten hub TFs(MYC,TP53,CEBPB,FOXM1,E2F1,EGR2,FOSL1,JUND,E2F7 and E2F8)are closely related to AILI,among which MYC,TP53,CEBPB,E2F1,JUND,and E2F7 have better diagnostic performance for AILI in its early stages.These findings further understand the pathogenesis of AILI and provide new diagnostic markers for the early diagnosis of AILI.