Epstein-Barr Virus oncoprotein super-enhancers control B cell growth

Super-enhancers are principal determinants of cell transcription, development, phenotype, and oncogenesis, not yet implicated in host-pathogen interactions. We found four Epstein-Barr virus (EBV) oncoproteins and five EBV-activated NF-?B subunits co-occupying thousand of enhancer sites in EBV-transformed lymphoblastoid cells (LCLs). Of these, 187 had markedly higher and broader histone H3K27ac signals characteristic of super-enhancer formation, and were designated “EBV super-enhancers”. EBV super-enhancer associated genes included MYC and BCL2, which enable LCL proliferation and survival. EBV super-enhancers were enriched for specific B cell transcription factor motifs and had high STAT5 and NFAT co-occupancy. EBV super-enhancer associated genes were more highly expressed than other LCL genes. Disruption of EBV super-enhancers by the bromo-domain inhibitor, JQ1, by conditional inactivation of an EBV oncoprotein or NF-?B, decreased MYC or BCL2 gene expression and arrested LCL growth. These findings provide novel insights into the mechanisms by which EBV causes lymphoproliferation and identify opportunities for therapeutic intervention. Overall design: ChIP-seq was used to define the BRD4 genome-wide landscape in GM12878 lymphoblastoid cells.