Genome-wide methylation and expression analyses reveal the epigenetic landscape of ras oncogene induced hepatic tumor in mouse
Objective To explore the characteristics of methylomics and transcriptomics in the occurrence and development of hepatic tumors induced by ras oncogene,and provide important data clues for studyingthe pathogenesis,male tenden-cy,andclinical diagnosis of liver cancer.Methods Whole genome DNA methylation and RNA transcriptome sequencing were performed in normal liver tissues of wild type C57BL/6J female and male mice,as well as in hepatic tumors and peri-tumor tissues of Hras12V transgenic female and male mice with the same genetic background.Combining whole genome DNA methylomics and transcriptomics,the gene expression profile regulated by DNA methylation during the occurence and development of hepatic tumors induced by rasoncogene was analyzed.Bioinformatics information analysis on gene expression profiles regulated by DNA methylation was performed by using enrichment analysis.Result Through compre-hensive analysis,it was found that the occurrence of hepatic tumors was related to methylation in the DNA promoter region,and among the deferentially expressed genes related to occurrence of hepatic tumors inducedby ras oncogene,si-lencing regulation with hypermethylation was the mian mechanism.There were genesregulated by common and specific methylation between genders,among which genes regulated by common methylation such as Rnf152,Gnmt,and Cxcl12,etc.were consistent with the expression regulation mechanism in human HCC.The results of bioinformatics analysis showed that the signaling pathways enriched by differentially methylated genes shared by male and female mice were mainly metabolic pathways,such as phenylalanine,arachidonic acid,glycine,etc.There were significant differences in the signal pathways enriched by differentially methylated genes between male and female mice,among which the retinol metabolism and RRAR signaling pathways were unique to female mice.Conclusion The occurrence of hepatic tumors in-duced by ras oncogene is associated with abnormal methylation in the promoter region,which is mainly dominated by hy-permethylation silencing.Bioinformatics enrichment analysis shows that methylation mainly regulates metabolic path-ways.The methylaton regulation of hepatic tumor occurrence varies between males and females,and the methylation reg-ulation of retinol metabolism and PPAR signaling pathway is unique to female mice.
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