Regulation of Viral Chromatin Architecture During EBV Latency

EB病毒（EBV）是一种人γ疱疹病毒，其感染约95%的群体，并且作为染色质相关的多拷贝附加体在记忆B细胞中保持潜伏。EBV感染与几种病理学有因果关系，包括传染性单核细胞增多症、不同类型的淋巴瘤和胃癌。EBV相关疾病的这种异质性可能反映了EBV在不同细胞类型和宿主细胞条件下采用的不同基因表达程序。表观遗传修饰和替代性病毒染色质构象有助于这些替代性病毒基因表达程序的建立和维持，这些程序被称为潜伏类型。尽管我们知道染色质组织因子如CTCF影响EBV附加体的表观遗传状态，但我们对控制EBV基因组可塑性和功能的机制以及EBV如何操纵宿主表观遗传机制以避免病毒潜伏启动子的完全表观遗传沉默知之甚少。该项目的长期目标是了解EBV如何劫持宿主表观遗传机制以建立潜伏感染，调节病毒和宿主基因表达。翻译后修饰调节几种细胞过程，包括宿主对病原体的反应。聚ADP-核糖基化由ADP-核糖的带负电荷的聚合物与受体蛋白的连接组成。该反应由聚（ADP-核糖）聚合酶（PARP）家族的成员催化。在以前的工作中，我们证明了PARP 1通过与病毒基因组相互作用来调节EBV复制。我们的初步工作提供了新的全基因组和生化数据，首次揭示了LMP 1激活PARP 1，PARP 1活性阻止EZH 2沉默病毒基因组。因此，我们假设EBV蛋白LMP 1通过PARP 1/EZH 2相互作用改变染色质结构来影响病毒基因表达。我们的项目旨在填补我们对EBV基因组表观遗传调控的理解中的差距。为了实现我们的目标，我们的目标是：1）PARP 1激活如何调节EBV潜伏期程序; 2）确定EZH 2是否在调节EBV潜伏期中发挥作用。该项目的完成将揭示EBV有助于维持和切换感染细胞中观察到的不同基因表达程序的新机制。它还将确定EBV感染和EBV相关恶性肿瘤的新的潜在治疗靶点。

Epstein-Barr virus (EBV) is a human gamma herpesvirus that infects approximately 95% of the population and remains latent in memory B cells as a chromatin-associated multicopy episome. EBV infection is causally associated with several pathologies including infectious mononucleosis, different types of lymphomas and gastric carcinoma. This heterogeneity in EBV-associated diseases may reflect the different gene expression programs that EBV adopts in different cell types and host-cell conditions. Epigenetic modifications and alternative viral chromatin conformations contribute to the establishment and maintenance of these alternative viral gene expression programs, which are referred to as latency types. Although we know that chromatin- organizing factors, such as CTCF, affect the epigenetic state of the EBV episome we know little about the mechanisms that govern EBV genome plasticity and function and how EBV manipulates the host epigenetic machinery to avoid complete epigenetic silencing of viral latent promoters. The long-term goal of this project is to understand how EBV hijacks host epigenetic machinery to establish a latent infection, regulating both viral and host gene expression. Post-translational modifications regulate several cellular processes including the host response against pathogens. Poly-ADP-ribosylation consists of the attachment of negatively charged polymers of ADP-ribose to acceptor proteins. The reaction is catalyzed by members of the Poly(ADP-ribose) polymerase (PARP) family. In previous work, we demonstrated that PARP1 regulates EBV replication by interacting with the viral genome. Our preliminary work provides new genome wide and biochemical data that reveals for the first time that LMP1 activates PARP1 and that PARP1 activity prevents EZH2 from silencing the viral genome. Thus, we hypothesize that the EBV protein LMP1 affects viral gene expression by altering chromatin structure through PARP1/EZH2 interaction. Our project aims to fill the gap in our understanding of the epigenetic regulation of the EBV genome. To achieve our goal, we aim to: 1) how PARP1 activation regulates EBV latency programs; and 2) determine if EZH2 plays a role in regulating EBV latency. Completion of this project will reveal new mechanisms by which EBV can contribute to maintain and switch between different gene expression programs observed in infected cells. It will also identify new potential therapeutic targets for EBV infection and EBV-associated malignancies.