KSHV is one of the two known human oncogenic gammaherpesvirus which induces oncogenesis in infected susceptible cells. In the HIV positive immunocompromised patients, pleural effusion lymphoma (PELs), Kaposi's sarcoma (KS) and Multicentric Castleman's Disease (MCD) are common. The associated human malignancy is a major contributor to increased mortality in developing countries in this population of HIV positive patients. This study will explore epigenetic mechanism by which KSHV is regulated in endothelial cells and KS infected tissue. We will be collaborating with investigators in Shanghai and Northwest China Xinjiang province where KS incidence is quite high. We will focus on three major aims to explore the hypothesis that gene regulation in KSHV infected KS tissue is controlled by specific epigenetic changes that occur on the KSHV genome in the infected human endothelial spindle cells. We expect that genomic modifications are endothelial cell specific, and would provide clues as to the distinct profiles of expression in the KS tissue and infected endothelial cells. We will determine the specific markers which represent the epigenetic landscape in KS tissue by chromatin immunoprecipitation using specific antibodies to acetylation and methylation marks on histones. We will also identify the overall gene expression profiles related to LANA, Rta and CSL/RBP-Jk expression and the regulatory mechanisms at the viral and cellular level. Conditional expression as well as RNAi strategies for modulation of expression of LANA, Rta and CSL/RBP-Jk will be used as well as genetic mutations in the viral genomes to determine the control mechanisms that are utilized to drive proliferation of the infected KS cells. The expression profiles will be determined by RNA-Seq and analyzed for unique genes that are regulated in the viral infected cells. These will then be validated using real-time PCR analysis of the specific mRNA transcripts, as well as immunohistochemistry and immunofluorescence analysis in KS tissue and infected endothelial cells. These studies will further our understanding of KSHV latency mechanisms and provide insights for therapeutic potential by targeting the pathways activated in the KS disease.
KSHV is a major human pathogen. It is associated with 3 major proliferative diseases in humans including pleural effusion lymphomas. In the proposed collaborative studies we will focus on the epigenetic regulation of the KSHV genome in KS tissue and endothelial infected cells. The results would provide unique and novel clues for targeted therapeutic development for treatment of KS disease.
|Sun, Rui; Tan, Xiaohua; Wang, Xing et al. (2017) Epigenetic Landscape of Kaposi's Sarcoma-Associated Herpesvirus Genome in Classic Kaposi's Sarcoma Tissues. PLoS Pathog 13:e1006167|
|Madireddy, Advaitha; Purushothaman, Pravinkumar; Loosbroock, Christopher P et al. (2016) G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV. Nucleic Acids Res 44:3675-94|
|Jha, Hem Chandra; Banerjee, Shuvomoy; Robertson, Erle S (2016) The Role of Gammaherpesviruses in Cancer Pathogenesis. Pathogens 5:|
|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|
|Sun, Zhiguo; Jha, Hem Chandra; Pei, Yong-Gang et al. (2016) Major Histocompatibility Complex Class II HLA-DR? Is Downregulated by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Lytic Transactivator RTA and MARCH8. J Virol 90:8047-58|
|Jha, Hem C; Pei, Yonggang; Robertson, Erle S (2016) Epstein-Barr Virus: Diseases Linked to Infection and Transformation. Front Microbiol 7:1602|
|Uppal, Timsy; Jha, Hem C; Verma, Subhash C et al. (2015) Chromatinization of the KSHV Genome During the KSHV Life Cycle. Cancers (Basel) 7:112-42|
|Saha, Abhik; Jha, Hem C; Upadhyay, Santosh K et al. (2015) Epigenetic silencing of tumor suppressor genes during in vitro Epstein-Barr virus infection. Proc Natl Acad Sci U S A 112:E5199-207|
|Gan, Jin; Wang, Chong; Jin, Yanling et al. (2015) Proteomic profiling identifies the SIM-associated complex of KSHV-encoded LANA. Proteomics 15:2023-37|
|Banerjee, Shuvomoy; Jha, Hem Chandra; Robertson, Erle S (2015) Regulation of the metastasis suppressor Nm23-H1 by tumor viruses. Naunyn Schmiedebergs Arch Pharmacol 388:207-24|
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