EBNA2 Drives Formation of New Chromosome Binding Sites and Target Genes for B-Cell Master Regulatory Transcription Factors RBP-jκ and EBF1

Epstein-barr virus (ebv) transforms resting b-lymphocytes into proliferating lymphoblasts to establish latent infections that can give rise to malignancies. we show here that ebv-encoded transcriptional regulator ebna2 drives the cooperative and combinatorial genome-wide binding of two master regulators of b-cell fate,namely ebf1 and rbp-jκ. previous studies suggest that these b-cell factors are statically bound to target gene promoters. in contrast,we found that ebna2 induces the formation of new binding for both rbp-jκ and ebf1,many of which are in close physical proximity in the cellular and viral genome. these newly induced binding sites co-occupied by ebna2-ebf1-rbp-jκ correlate strongly with transcriptional activation of linked genes that are important for b-lymphoblast function. conditional expression or repression of ebna2 leads to a rapid alteration in rbp-jκ and ebf1 binding. biochemical and shrna depletion studies provide evidence for cooperative assembly at co-occupied sites. these findings reveal that ebna2 facilitate combinatorial interactions to induce new patterns of transcription factor occupancy and gene programming necessary to drive b-lymphoblast growth and survival. © 2016 lu et al.