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Epigenetic modifications play a pivotal role in the expression of the genes of Epstein-Barr virus (EBV). We found that de novo EBV infection of primary B cells caused moderate induction of enhancer of zeste homolog 2 (EZH2), the major histone H3 lysine 27 (K27) methyltransferase. To investigate the role of EZH2, we knocked out the EZH2 gene in EBV-negative Akata cells by the CRISPR/Cas9 system and infected the cells with EBV, followed by selection of EBV-positive cells. During the latent state, growth of EZH2-knockout (KO) cells was significantly slower after infection compared to wild-type controls, despite similar levels of viral gene expression between cell lines. After induction of the lytic cycle by anti-IgG, KO of EZH2 caused notable induction of expression of both latent and lytic viral genes, as well as increases in both viral DNA replication and progeny production. These results demonstrate that EZH2 is crucial for the intricate epigenetic regulation of not only lytic but also latent gene expression in Akata cells. IMPORTANCE The life cycle of EBV is regulated by epigenetic modifications, such as CpG methylation and histone modifications. Here, we found that the expression of EZH2, which encodes a histone H3K27 methyltransferase, was induced by EBV infection; therefore, we generated EZH2-KO cells to investigate the role of EZH2 in EBV-infected Akata B cells. Disruption of EZH2 resulted in increased expression of EBV genes during the lytic phase and, therefore, efficient viral replication and progeny production. Our results shed light on the mechanisms underlying reactivation from an epigenetic point of view and further suggest a role for EZH2 as a form of innate immunity that restricts viral replication in infected cells.

Regulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells