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.
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.
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|Liu, Dongcheng; Wang, Yan; Yuan, Yan (2018) Kaposi's Sarcoma-Associated Herpesvirus K8 Is an RNA Binding Protein That Regulates Viral DNA Replication in Coordination with a Noncoding RNA. J Virol :|
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|Lang, Fengchao; Sun, Zhiguo; Pei, Yonggang et al. (2018) Shugoshin 1 is dislocated by KSHV-encoded LANA inducing aneuploidy. PLoS Pathog 14:e1007253|
|Pei, Yonggang; Singh, Rajnish Kumar; Shukla, Sanket Kumar et al. (2018) Epstein-Barr Virus Nuclear Antigen 3C Facilitates Cell Proliferation by Regulating Cyclin D2. J Virol 92:|
|Tso, For Yue; Kossenkov, Andrew V; Lidenge, Salum J et al. (2018) RNA-Seq of Kaposi's sarcoma reveals alterations in glucose and lipid metabolism. PLoS Pathog 14:e1006844|
|Mawhinney, Matthew T; Liu, Runcong; Lu, Fang et al. (2018) CTCF-Induced Circular DNA Complexes Observed by Atomic Force Microscopy. J Mol Biol 430:759-776|
|Li, Yuqing; Zhong, Canrong; Liu, Dawei et al. (2018) Evidence for Kaposi Sarcoma Originating from Mesenchymal Stem Cell through KSHV-induced Mesenchymal-to-Endothelial Transition. Cancer Res 78:230-245|
|Aneja, Kawalpreet K; Yuan, Yan (2017) Reactivation and Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus: An Update. Front Microbiol 8:613|
|Chen, Horng-Shen; De Leo, Alessandra; Wang, Zhuo et al. (2017) BET-Inhibitors Disrupt Rad21-Dependent Conformational Control of KSHV Latency. PLoS Pathog 13:e1006100|
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