Systematic investigation reveals extensive Epstein-Barr virus transcriptional regulation of the human genome.

We systematically investigate interactions between Epstein-Barr virus (EBV) transcriptional regulators (viral transcriptional regulators [vTRs]) and the human genome. Starting with 16 known and candidate vTRs, we identify nine whose introduction into human cells results in substantial alterations to host gene expression. Genome-scale profiling of vTR binding, chromatin accessibility alterations, and gene expression impact reveals extensive EBV functional interactions with the human genome, including >100,000 vTR binding events impacting almost a quarter of human genes. BMRF1 emerges as a potent regulator, impacting >7,000 genes and altering >37,000 chromatin regions. Our results reveal that EBV RTA interacts with and stabilizes the binding of human RBPJ. Network analysis reveals that many human genes are targeted by multiple EBV-vTRs, highlighting the vast coordinated impact of EBV on human gene expression. This study provides a valuable, extensive resource for examining EBV-induced alterations to human gene regulation, with data available on multiple platforms.