Genome-wide mapping of EBV-induced genomic variationsidentifies the role of MUC19 in EBV latency

Abstract

Epstein-Barr virus (EBV) infects over 95% of the worlds population and is tightly associated with multiple human malignant diseases. As the first discovered human oncovirus, EBV is known to induce genomic instability by promoting various types of genomic modifications in host chromosomes. However, the mechanisms through which EBV interacts with the host genome and regulates cellular gene expression in genomic modifications are not yet fully elucidated. In this study, we conducted primary EBV infection in B cells and performed the analyses of copy number variants using whole genome sequencing. After comparing to other distinct B cells with varying EBV infection backgrounds, we identified susceptible regions and unveiled critical host factors induced by EBV infection on chromosomes. Combined with the genome-wide transcriptomic analyses, we found that the mucin gene MUC19 is distinctively activated by EBV infection and MUC19 promotes oncogenesis through the activation of mTOR signaling in lymphoblastoid cell lines (LCLs). Further results indicate that EBV nuclear antigen 1 (EBNA1) binds to multiple regions within MUC19 and enhances the expression of MUC19. Moreover, sequence alignment has shown intriguing motif homology between the basic repeat unit of MUC19 and EBV genome, suggesting the potential of EBV-specific integration. To conclude, our study maps the genomic perturbations induced by EBV primary infection and offers new insights into the oncogenic roles of MUC19 during EBV latency.