Herpesvirus-Chromatin-Programmierung während der De-Novo-Infektion

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Nuclear entry of a non-chromatinized, epigenetically naïve DNA molecule is a central event in all herpesvirus infections. Following nuclear delivery, viral episomes can either activate the lytic gene expression cascade, leading to production of viral progeny and host cell death, or acquire latent chromatin states that mediate selective and reversible silencing of lytic genes. Whereas latent chromatin allows the viral genome to persist in a dormant state until a reactivation signal is received, antiviral host defences promote constitutively repressive chromatin states to globally supress invading DNA. If the virus fails to escape or manipulate these defences, viral episomes are permanently silenced or cleared.To date, the chromatin factors and epigenetic pathways governing successful establishment of latent chromatin are only partially understood. Given their evolutionary relationship, we hypothesise that as of yet undiscovered and fundamental principles are shared among different herpesviruses. To address this hypothesis, we here will perform a comparative analysis of two human herpesviruses: The gammaherpesvirus Kaposi sarcoma-associated herpesvirus (KSHV) and the alphaherpesviruses varicella zoster virus (VZV). Based on our previous observations, we hypothesize that both viruses exploit default host pathways that have evolved to rapidly recruit polycomb repressive complexes (PRC) to CpG-rich DNA molecules devoid of DNA methylation. Instead of constitutive heterochromatinization that may be imposed by components of PML nuclear bodies (PML-NBs), PRC recruitment then allows viral episomes to acquire facultative heterochromatin states to establish and maintain latency. While we therefore postulate PRC-mediated suppression to be a common denominator of latency, we also expect that initial assembly as well as maturation of viral chromatin proceed in a spatially and/or temporally distinct fashion for each virus. We will employ relevant in vitro latency models, transcriptome/epigenome analyses and live cell imaging to perform a spatiotemporal investigation of the latency establishment phase to decipher the mechanisms that govern viral chromatin programming, and to identify the key viral and cellular factors involved in this process. In a putative second funding period, we plan to extend our findings to other viruses with the explicit goal of developing a unified model of early chromatin regulation in DNA virus infection.