KSHV is the causative agent of all forms of Kaposi’s sarcoma (KS). KS is the most common form of cancer in males in sub-Saharan Africa and HIV-AIDS patients. KSHV is also responsible for several lymphoid disorders, including pleural effusion lymphoma (PEL) and Castleman’s disease. Long-term latent infection in B- lymphocytes and persistent infection in endothelial cells is thought to be a major driving force for KSHV oncogenesis. KSHV pathogenesis depends on viral persistence and highly regulated gene expression during latent infection. We have focused on epigenetic and chromatin organizing factors that regulate viral gene expression and maintain stable latency in KSHV infected tumor cells. Here, we expand our studies on the X- ray crystal structures of KSHV encoded LANA to explore its propensity to form higher-order oligomeric complexes that are necessary for episome maintenance. We investigate the relationship between LANA oligomerization and chromatin organization mediated by cellular factors, including the chromatin organizing factors CTCF and cohesins and the heterochromatin regulatory factors DAXX and EZH2. We also investigate how the bromodomain proteins BRD2 and BRD4 bind to the basic patch of the LANA DNA binding domain, and how these BET-proteins function to facilitate LANA chromatin binding, and epigenome architecture. We discovered that small molecule inhibitors of BET proteins, like JQ1, are potent activators of KSHV lytic gene expression, and investigate how disruption of BRD2 or BRD4 function alters the KSHV epigenome. Finally, we analyze transcriptomic data from KS lesions to reveal a central role of the Unfolded Protein Response (UPR) in regulating KSHV latency. We find that inducers of the UPR disrupt KSHV latency through a mechanism involving the rapid proteolytic cleavage of the Cohesin subunit RAD21. We propose that RAD21 cleavage functions as a rapid release trigger for lytic reactivation, and therefore represents a novel chromatin- conformation sensor mechanism for UPR stress. The potential mechanistic relationship between UPR and the RAD21-BRD2/4-LANA axis will be investigated. Finally, we explore how pharmacological inhibition of UPR may modulate KSHV gene expression to ameliorate KS progression and pathogenesis. These studies will advance our knowledge of KSHV infection opportunities for therapeutic intervention in KSHV-associated disease.