Epigenetic Regulation of Gammaherpesviruses: A Focus on Kaposi's Sarcoma-Associated Herpesvirus (KSHV/HHV-8)

Gammaherpesviruses are ubiquitous in nature and infect a broad range of animal species. They have a biphasic life cycle that alternates between latent and lytic phases and are able to maintain a persistent infection for long periods. Both Epstein-Barr virus (EBV) and Kaposi's Sarcoma-associated Herpesvirus (KSHV) are oncogenic viruses that are known to cause several lymphoproliferative diseases in humans. EBV and KSHV persist as viral episomes that orchestrate very tightly controlled programs of gene expression, whereby a distinct subset of viral genes is expressed during the latent phase. Various stimuli can induce lytic reactivation of both viruses, which results in expression of lytic genes and is accompanied by changes in histone modification and DNA methylation. CTCF and cohesin binding provide segregation of chromatin loops as well as cross talk between different regions of the genome. Furthermore, noncoding RNAs (ncRNAs) provide an additional layer of epigenetic regulation for gammaherpesviruses. MAPit, a single-molecule footprinting assay, has revealed the occurrence of several subtypes of chromatin architecture at various KSHV promoters, suggesting the presence of heterogeneity within the population of KSHV viral episomes. In this chapter, we discuss the epigenetic regulation of gammaherpesviruses during latency and lytic reactivation, with a primary focus on KSHV.