Transcriptional regulation of gene modules in Epstein-Barr virus

Epstein-Barr Virus (EBV) establishes life-long latent infection in >90% of adults and is a causal agent for diverse cancers and autoimmune diseases. EBV has a complex life cycle in multiple different tissue types that involve dynamic variations in viral gene expression. These gene expression changes account for the success of the virus in long-term persistence and evading host immune control, as well as its potential for driving cancer evolution and autoimmune disease. Here, we review some of the salient features of EBV gene regulation highlighting the many variations of viral transcription. We review recent advances in our understanding of the factors that bind and regulate EBV gene expression. Based on this diversity of viral transcription patterns, we propose that EBV genome consists of gene modules regulated by local promoter-proximal transcription factor combinations that are further regulated by distal regulatory interactions among the various modules that interact through architectural factors, such as CTCF and cohesion. These modules are likely to represent chromatin architectural domains, and can also interact with host chromosome domains that further regulate viral and host gene expression. We propose that this gene regulatory hierarchy provides EBV with necessary plasticity for viral persistence, as well as a strong potentiator for cancer and autoimmune disease.