Epigenetic Regulation of Viral Gene Expression

Abstract

Kaposi’s sarcoma associated herpesvirus (KSHV) causes multiple malignancies in mainly immunocompromised individuals. KSHV exists in two distinct phases within its host: latent and lytic. During its latent phase, small amounts of viral genes are expressed while most of the viral genome exists in a highly condensed chromatin state. The virus can undergo lytic reactivation where the chromatin is opened up to express many viral genes to produce progeny virions. Multiple viral factors influence the virus’ transition between these two latent-lytic stages. ORF59, a DNA processivity factor, and PAN RNA, a long noncoding RNA, are important in altering the viral chromatin to remove repressive marks to promote lytic reactivation. The histone demethylases UTX and JMJD3 are also responsible for removing repressive marks from the viral genome. Previous studies have shown that PAN RNA interacts with UTX and JMJD3 as well as ORF59. This interaction prompted the question, does ORF59 also interact with UTX and JMJD3 and does this binding occur through an RNA intermediate? Protein-protein interaction studies were performed to determine that UTX and JMJD3 bind to ORF59. Our results also suggest that PAN RNA is required for the interaction of UTX and JMJD3 with the viral processivity factor ORF59. Given the importance of these factors in transitioning the virus into its lytic phase, identifying this interaction could help lead to the prevention of viral lytic reactivation.