Abstract
Hemorrhagic disease caused by grass carp reovirus (GCRV) has severely threatened the grass carp (Ctenopharyngodon idella) cultivation industry. It is noteworthy that the resistance against GCRV infection was reported to be inheritable, and identified at both individual and cellular levels. Therefore, this work was inspired and dedicated to unravel the molecular mechanisms of fate decision post GCRV infection in related immune cells. Foremost, the resistant and susceptible CIK (C. idella kidney) monoclonal cells were established by single cell sorting, subculturing and infection screening successively. RNA-Seq, MeDIP-Seq and small RNA-Seq were carried out with C1 (CIK cells), R2 (resistant cells) and S3 (susceptible cells) groups. It was demonstrated that genome-wide DNA methylation, mRNA and microRNA expression levels in S3 were the highest among three groups. Transcriptome analysis elucidated that pathways associated with antioxidant activity, cell proliferation regulation, apoptosis activity and energy consuming might contribute to the decision of cell fates post infection. And a series of immune-related genes were identified differentially expressed across resistant and susceptible groups, which were negatively modulated by DNA methylation or microRNAs. To conclude, this study systematically uncovered the regulatory mechanism on the resistance from epigenetic perspective and provided potential biomarkers for future studies on resistance breeding.
Highlights
In a former study conducted with 10, 000 grass carp reovirus (GCRV) infected fish, the resistant individuals were identified within familial groups, indicating that GCRV resistance trait has high heritability[4]
By integrated analysis of DNA methylation and miRNAs with gene expression, the regulatory mechanism in C. idella against GCRV was revealed from the epigenetic perspective, and multiple functional genes modulated by DNA methylation and miRNAs were excavated as the potential biomarkers contributing to breeding for disease resistance (Supplementary Fig. S1)
Eight cell strains were preliminary identified as susceptible cells which exerted conspicuous cytopathic effect (CPE) at 6 h post GCRV infection, mass mortality after 48 h as well as scarcely any survival 72 h later
Summary
In a former study conducted with 10, 000 GCRV infected fish, the resistant individuals were identified within familial groups, indicating that GCRV resistance trait has high heritability[4]. DNA methylation, a key epigenetic modification, generally occurs in the fifth position of cytosine (5-methylcytosine, 5-mC) and scatters over the gene body[7]. Accumulating evidences have demonstrated that the diversiform diseases result from aberrant DNA methylation[15, 16] It could provide valuable insights into pathogenesis in cancer, mental disorders as well as several autoimmune disorders by revealing the methylation patterns of functional genes especially over genome-wide[17,18,19,20]. By integrated analysis of DNA methylation and miRNAs with gene expression, the regulatory mechanism in C. idella against GCRV was revealed from the epigenetic perspective, and multiple functional genes modulated by DNA methylation and miRNAs were excavated as the potential biomarkers contributing to breeding for disease resistance (Supplementary Fig. S1). This study undoubtedly provided an original thought into pathogenesis researches on hemorrhagic disease in C. idella
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