TY - JOUR T1 - Methionine Metabolism Controls the B-cell EBV Epigenome and Viral Latency JF - bioRxiv DO - 10.1101/2022.02.24.481783 SP - 2022.02.24.481783 AU - Rui Guo AU - Jin Hua Liang AU - Yuchen Zhang AU - Michael Lutchenkov AU - Zhixuan Li AU - Yin Wang AU - Vicenta Trujillo-Alonso AU - Rishi Puri AU - Lisa Giulino-Roth AU - Benjamin E. Gewurz Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/02/24/2022.02.24.481783.abstract N2 - Epstein-Barr virus (EBV) subverts host epigenetic pathways to switch between viral latency programs, colonize the B-cell compartment and reactivate. Within memory B-cells, the reservoir for lifelong infection, EBV genomic DNA and histone methylation marks restrict gene expression. But, this epigenetic strategy also enables EBV-infected tumors, including Burkitt lymphomas to evade immune detection. Little is known about host cell metabolic pathways that support EBV epigenome landscapes. We therefore used amino acid restriction, metabolomic and CRISPR approaches to identify that an abundant methionine supply, and interconnecting methionine and folate cycles, maintain Burkitt EBV gene silencing. Methionine restriction, or methionine cycle perturbation, hypomethylated EBV genomes, de-repressed latent membrane protein and lytic gene expression. Methionine metabolism also shaped EBV latency gene regulation required for B-cell immortalization. Dietary methionine restriction altered murine Burkitt xenograft metabolomes and de-repressed EBV immunogens in vivo. These results highlight epigenetic/immunometabolism crosstalk supporting the EBV B-cell lifecycle and suggest therapeutic approaches.HighlightsMethionine metabolism is critical for Epstein-Barr virus B-cell latencyExtensive cross-talk enables methionine metabolism to control the EBV epigenomeMethionine restriction also impairs EBV-driven human B-cell immortalizationDietary methionine restriction unmasks EBV antigens in Burkitt xenografts in vivoCompeting Interest StatementThe authors have declared no competing interest. ER -