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

Summary We systematically investigate interactions between Epstein-Barr virus (EBV) 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 determination of vTR genomic binding events and alterations to chromatin accessibility reveals a detailed map of EBV’s functional interactions with the human genome, including >100,000 vTR binding events impacting almost a quarter of all human genes. BMRF1 emerges as a potent regulator, impacting >7,000 genes and altering >37,000 chromatin regions. Our results provide new evidence 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. Competing Interest Statement The authors have declared no competing interest. Footnotes We have slightly updated the writing in this manuscript to reflect the version now submitted for peer review.