KSHV is a human gammaherpesvirus that is the causative agent of Kaposi's sarcoma (KS), and tightly associated with pleural effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). Establishment of latent infection in B-lymphocytes and persistent infection in endothelial cells is thought to be a major driving force for KSHV-associated disease. Establishment of latent infection requires the formation of a stable circular minichromosome that expresses a limited set of viral genes. The mechanisms that establish minichromosome formation and restrict gene expression to the latency class are not well understood. Our previously published studies indicate that chromatin boundary factors, like CTCF, organize viral chromosome structure and histone modification patterns important for genome stability and restricted gene expression. CTCF interacts with cohesins (e.g. SMCl, SMC3, Rad21) to form higher order DNA conformations that are important for chromosome transmission during cell division and for coordinated transcription regulation. Recent studies from our group revealed that CTCF-cohesins mediate Interactions between the latent and lytic control regions of KSHV genomes in latently infected PEL cells. New preliminary data indicate that lytic immediate early genes are coordinately regulated through a chromatin structure involving CTCF and cohesins, and that cohesins are required for suppression of lytic gene transcription. Furthermore, CTCF binding sites are located in close proximity to RBP-jK sites at the lytic and latent control regions. Since RBP-jK is a primary target of KSHV immediate early protein Rta and latency maintenance protein LANA, we will explore how these proteins (e.g. RBP-jK, Rta, K8, and LANA) may interact with arid regulate CTGF-cohesion function. We will also investigate the role of host intrinsic defense proteins in regulating viral chromatin assembly. Finally, we will explore the role of LANA and KSHV infection on viral and host chromosome structure and epigenetic: modifications.
These aims will synergize with projects 1 &2 of this program project, and provide both molecular and genome-wide analyses of chromatin control mechanisms during the early stages of KSHV infection and in the establishment of KSHV latency.

Public Health Relevance

Chromatin structure and organization represents an important level of host-virus interaction. We propose to investigate the role of chromatin assembly on the fate of de novo KSHV infection. This work will provide new insight into the mechanism of chromatin control of viral gene expression and genome propagation, and may reveal new targets for therapeutic intervention in KSHV-associated disease and cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-2)
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University of Pennsylvania
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Shukla, Sanket Kumar; Jha, Hem Chandra; El-Naccache, Darine W et al. (2016) An EBV recombinant deleted for residues 130-159 in EBNA3C can deregulate p53/Mdm2 and Cyclin D1/CDK6 which results in apoptosis and reduced cell proliferation. Oncotarget 7:18116-34
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