Abstract IA10: Epigenetic remodeling of host metabolic pathways by Epstein-Barr virus (EBV) immortalization

Abstract

Abstract Epstein-Barr virus (EBV) reprograms host metabolism and gene expression during B-cell immortalization through a highly orchestrated process. The regulatory mechanisms coordinating this reprogramming are not fully elucidated but reflect important events in viral oncogenesis. One clue to this coordinate regulation is provided by the viral-encoded tegument protein BNRF1 that functions in viral chromatin assembly during primary infection and shares extensive structural similarity to a purine biosynthetic enzyme FGARAT (also called PFAS). FGARAT shows strong evolutionary conservation from bacteria to human. Orthologues of BRNF1 are found in all gamma herpesviruses, including KSHV ORF75, and share the common function of disarming components of the PML-nuclear body (PML-NB) and its antiviral functions. We have previously shown that the BNRF1 interacts with the histone H3.3 chaperone DAXX and displaces its interaction with ATRX. ATRX is thought to target Daxx-H3.3 to GC-rich repetitive DNA to repress viral and host telomeric transcription. We found that the BNRF1-DAXX complex changes these functions to facilitate viral gene expression during primary infection, enabling the establishment of EBV latency. However, it is not yet known how the viral FGARAT homology is linked to cellular metabolism and purine biosynthesis. Using metabolomics mass spectrometry, we provide new data indicating that the metabolic pathways are among the most significantly perturbed by EBV during B-cell immortalization. Integrating gene expression (RNA-Seq), chromatin accessibility (ATAC-Seq), and EBV transcription factor binding (ChIP-Seq) we identified several cellular metabolic genes, including adenine deaminase (ADA) and arginosuccinate synthase (ASS1), as a direct target of EBV transcriptional regulation during EBV immortalization. We find that EBV nuclear antigen EBNA1 binds directly to the ADA transcriptional regulatory regions and induces epigenetic changes at this locus. Failure to activate ADA compromises B-cell immortalization. The relationship between BNRF1, EBNA1, and nucleotide metabolism during EBV immortalization will be discussed. These findings suggest that EBV captured a highly conserved purine biosynthetic enzyme to coordinate epigenetic reprogramming with nucleotide metabolism during EBV induced B-cell immortalization. Citation Format: Jason Lamontagne, Andreas Wiedmer, Paul M. Lieberman. Epigenetic remodeling of host metabolic pathways by Epstein-Barr virus (EBV) immortalization [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA10.