Epigenomic Drivers of EBV Epithelial Cancers

项目1 -项目概要 该项目的长期目标是确定EBV如何在EBV中建立致癌潜伏表观基因组- 相关的上皮癌，并利用这些信息来开发新的治疗策略， 上皮癌中的EB病毒潜伏感染所有的EB病毒癌症都有一个共同的特征， 表达一组有限的病毒致癌基因的基因组。EB病毒上皮癌也有区别于 CpG岛甲基化表型（CIMP）EB病毒潜伏感染在驱动CIMP中的作用， CIMP在调节致癌EBV潜伏期中的作用尚未完全阐明，但对于理解EBV至关重要 致癌作用在目的1中，我们建议调查EB病毒潜伏感染如何促进CIMP。我们将测试 EBNA 1驱动的附加体维持诱导PARP 1依赖性DNA损伤的特定假设 驱动CIMP的响应。在与项目2的合作中，我们将研究PARP 1和UHRF 1在以下方面的作用： 位点特异性病毒和宿主DNA甲基化的形成。我们将与项目3合作， PI 3 K活化在控制上皮癌复制应激中的作用。在目标2中，我们将检验假设 CIMP和其他体细胞变化，如PI 3 K和ARID 1A突变，促进了病毒的形成。 II型潜伏期。与项目2合作，我们将研究CTCF和CIMP在EBV 3D中的作用 构象在项目3中，我们将研究代谢变化如何促进II型潜伏期的建立 在上皮癌中。最后，我们将与项目2、3和所有核心合作， 治疗EBV（+）上皮癌的治疗方法。为此，我们开发了新的小分子 抑制剂和EBV上皮癌小鼠模型，以更好地了解这些机制和测试 治疗策略项目1的总体假设是EBV上皮恶性肿瘤 依赖于建立一个独特的表观遗传状态，涉及CpG甲基化表型（CIMP） 这种表观遗传状态的关键调节因子是EBV上皮癌发生的治疗靶点。

PROJECT 1 – PROJECT SUMMARY The long-term goal of this project is to determine how EBV establishes an oncogenic latent epigenome in EBV- associated epithelial cancers and to leverage this information to develop new therapeutic strategies to target EBV latent infection in epithelial cancers. All EBV cancers share the common feature of maintaining latent viral genomes that express a restricted subset of viral oncogenes. EBV epithelial cancers also have the distinguishing feature of CpG Island Methylation Phenotype (CIMP). The role of EBV latent infection in driving CIMP, and the role of CIMP in regulating oncogenic EBV latency are not fully elucidated, but critical for understanding EBV carcinogenesis. In Aim 1, we propose to investigate how EBV latent infection promotes CIMP. We will test the specific hypothesis that EBNA1-driven episome maintenance induces a PARP1-dependent DNA-damage response that drives CIMP. In collaboration with Project 2, we will investigate the role of PARP1 and UHRF1 in the formation of site-specific viral and host DNA methylation. In collaboration with Project 3, we will explore the role of PI3K activation in controlling replication stress in epithelial cancers. In Aim 2, we will test the hypothesis that CIMP and other somatic changes, such as PI3K and ARID1A mutations, facilitate the formation of a viral type II latency. In collaboration with Project 2, we will examine the role of CTCF and CIMP on EBV 3D conformation. With Project 3, we will investigate how metabolic changes favor establishment of type II latency in epithelial cancers. Finally, we will work in collaboration with Projects 2, 3 and all Cores to identify new therapeutic approaches to treat EBV(+) epithelial cancers. To this end, we have developed new small molecule inhibitors and mouse models of EBV epithelial cancers to better understand these mechanisms and test therapeutic strategies. The overarching hypothesis of Project 1 is that EBV epithelial malignancies depend on the establishment of a distinct epigenetic state involving CpG methylator phenotype (CIMP) and that key regulators of this epigenetic state are therapeutic targets in EBV epithelial carcinogenesis.