Cross-species chromatin interactions drive transcriptional rewiring in Epstein-Barr virus-positive gastric adenocarcinoma

Epstein-Barr virus (EBV) is associated with several human malignancies including 8-10% of gastric cancers (GCs). Genome-wide analysis of 3D chromatin topologies across GC lines, primary tissue and normal gastric samples revealed chromatin domains specific to EBV-positive GC, exhibiting heterochromatin-to-euchromatin transitions and long-range human-viral interactions with non-integrated EBV episomes. EBV infection in vitro suffices to remodel chromatin topology and function at EBV-interacting host genomic loci, converting H3K9me3(+)heterochromatin to H3K4me1(+)/H3K27ac(+)bivalency and unleashing latent enhancers to engage and activate nearby GC-related genes (for exampleTGFBR2andMZT1). Higher-order epigenotypes of EBV-positive GC thus signify a novel oncogenic paradigm whereby non-integrative viral genomes can directly alter host epigenetic landscapes ('enhancer infestation'), facilitating proto-oncogene activation and tumorigenesis. Genome-wide analysis of 3D chromatin topologies across gastric cancers suggests that Epstein-Barr virus infection may induce the epigenetic rewiring of EBV-positive tumors through human-viral chromatin interactions, a phenomenon termed 'enhancer infestation'.