Our laboratory studies the mechanisms of epigenetic regulation of DNA virus infection. We are interested in the mechanisms by which human cells sense foreign DNA in the cell nucleus and activate transcription of innate response genes and epigenetically silence the foreign DNA. Herpes simplex virus has a double-stranded DNA genome that has no histones associated with it in the virion. Upon entry into cells, the nucleocapsid is transported to the nuclear pore where the dsDNA genome is released into the nucleus. The host cell rapidly silences the viral lytic genes by loading of heterochromatin on the viral genome. In epithelial cells viral proteins reverse the epigenetic silencing, but in neuronal cells viral non-coding RNAs promote lytic gene silencing with facultative heterochromatin.

Relief of Epigenetic Silencing in Epithelial Cells. The HSV VP16 protein is delivered in the cytoplasm with the nucleocapsid and localizes to the nucleus where it binds to the cell Oct-1 protein, which binds to the viral immediate-early proteins and this complex recruits the cell host cell factor 1 (HCF-1) to the complex. HCF-1 recruits numerous histone modification enzymes and chromatin remodeling complexes to reduce histone occupancy, remove heterochromatin modifications and increase euchromatin modifications and activate IE gene transcription. We have shown that the VP16-Oct1-HCF-1 complex assembles on viral DNA in association with the nuclear lamina and we are currently mechanism of this novel intranuclear localization mechanism.