Genome-wide mapping of EBV-induced genomic variations identifies the role of MUC19 in EBV latency.

Epstein-Barr virus (EBV) infects over 95% of the world's 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. The results showed genomic regions susceptible to EBV-induced mutations and unveiled MUC19 to be a critical host factor in EBV latency, which was distinctively activated transcriptionally upon EBV infection. Finally, we identified the intrinsic tandem repeats in MUC19 to be its functional domain, which promotes cell survival and cell cycle through activating mechanistic target of rapamycin (mTOR) signaling in EBV-positive cells. Further results indicate that EBV nuclear antigen 1 binds to the promoter of the MUC19 gene and enhances its expression. In conclusion, these results provide novel insights into the roles of MUC19 in EBV latency, highlighting its potential as a promising therapeutic target for the treatment of EBV-associated lymphomas.IMPORTANCEGenomic instability is a hallmark of cancer. EBV contributes to host genomic instability after primary infection. This study maps the EBV-induced genomic variations using deep whole genome sequencing and identifies the critical factor MUC19, which is one of the most understudied genes, with a genomic sequence exceeding 177 kbp that encodes a protein over 800 kD. In this study, we revealed that EBV induced the duplicated copy number variants of the MUC19 gene and enhanced its expression, which further promotes cell survival and cell cycle via mTOR signaling. Overall, this study maps the genomic perturbations induced by EBV primary infection and offers new insights into the critical role of MUC19 in EBV latency.