Mechanisms of oral epigenetic reprogramming in tumorviral pathogenesis

描述（由申请人提供）：我们对微生物组复杂性的了解不断增加，揭示了致病后果的巨大潜力。这些相互作用的影响可能在口腔的进一步研究中得到最好的揭示。机会性肿瘤病毒的激活会导致口腔发病率和恶性肿瘤，从而加重口腔疾病负担。越来越多的证据表明，表观遗传修饰是肿瘤病毒发病机制的核心，可调节1)宿主抗病毒反应和2)病毒再激活、复制和病毒癌蛋白的表达。DNA肿瘤病毒在口腔上皮中复制，并在口腔液体中脱落，这表明复制和从潜伏期重新激活正在进行中。一个基本的问题是缺乏关于体内潜伏到溶解转化的知识。为什么

DESCRIPTION (provided by applicant): Our increased understanding of the complexity of the microbiome has revealed great potential for pathogenic consequences. The effects of these interactions may be best revealed in further study of the oral cavity. The oral disease burden is exacerbated by activation of opportunistic tumorviruses resulting in oral morbidity and malignancy. Accumulating evidence suggests that epigenetic modifications are at the core of tumorviral pathogenesis modulating 1) host antiviral response and 2) viral reactivation, replication and expression of viral oncoproteins. DNA tumorviruses replicate in oral epithelia and are shed in oral fluids, inferring that replication and reactivation from latency are ongoing. A fundamental question is lack of knowledge regarding the latent to lytic transition in vivo. Why are these viruses so successful in the mouth? We suggest that certain oral bacteria act as environmental triggers that allow for oral epigenetic reprogramming. We now have compelling evidence that oral bacterial products deregulate chromatin modifying enzymes, activate histone marks H3Ac and H4Ac, modify tumorviral promoters, and enhance viral gene expression associated with reactivation and oncogenesis in a species specific manner. Further, these bacterial products diminished the HDAC-associated antiviral interferon response. Collectively, these findings led us to hypothesize that within DNA tumorvirus infected cells, oral bacterial products alter the epigenetic landscape to enhance viral replication and alter cellular innate immune responses in the oral cavity. To test this hypothesis, we will focus on the identification of epigenetic elements central to bacterial modulation of early events in tumorviral pathogenesis. The study goals are to determine: (1) how the common oral pathogen P. gingivalis facilitates viral chromatin modifications critical to reactivation and oncogene expression (SA1 in vitro) (2) modification of host chromatin and gene expression central to the antiviral response (SA2 in vitro) and (3) in vivo correlates of active tumorviral chromatin and concurrent oral bacterial infections (SA3 in vivo). We will employ both standard and modern molecular methods, such as RNA-seq and ChIP-seq, together with targeted inhibition of epigenetic cellular processes to discern the mechanisms of viral chromatin regulation in Pg treated cells. We are uniquely positioned to accomplish these studies at UNC with leading expertise in epigenetics, oral medicine, virology, bacteriology, and computational analysis.