Regulation of EBV Latency by Chromosome Conformation

描述（由申请人提供）： 摘要 PI：意大利 项目：1 K99 AI 099153 -01标题：通过染色体构象调节EBV潜伏期登录号：3399731 ================== 注意事项：本摘要摘自应用程序，未经SRA验证。当应用程序扫描过程出现问题时，提取的文本可能不正确或不完整。 ================== EB病毒是一种感染B淋巴细胞的人类γ疱疹病毒。EB病毒潜伏感染与包括伯基特淋巴瘤（BL）和鼻咽癌（NPC）在内的几种人类恶性肿瘤有关。在潜伏期期间，EBV能够采用至少四种不同的基因表达程序，称为潜伏期类型。这些基因表达程序受替代启动子利用的调控。由于潜伏类型具有差异免疫原性，因此控制病毒基因表达和启动子选择是EBV建立长期感染的关键步骤。虽然已经取得了进展，但调控EBV基因表达的机制尚未阐明。围绕EBV潜伏启动子的染色质的分析显示，不同的表观遗传模式对应于不同的潜伏类型。此外，我们发现细胞因子CTCF结合在EBV基因组的几个关键区域，并调节启动子选择和病毒基因表达。我们还证明了CTCF可以促进病毒启动子和EBV复制起点之间的交替染色质环，表明染色质结构可以有助于调节EBV潜伏类型。该提案结合经典的生物化学方法学和染色体构象分析，试图揭示EBV基因组的三维结构在不同潜伏类型的病毒基因表达调控中的作用。本研究的目的是使用这种新的方法：1）确定CTCF/Cohesin相互作用在潜伏感染期间EBV高阶染色质结构调节中的作用; 2）确定病毒蛋白EBNA 1在EBV基因组构象调节中的作用; 3）确定EBNA 1是否促进病毒-宿主和宿主-宿主染色体之间的染色体间DNA相互作用;和4）测试PARP 1抑制是否使EBV染色体结构和病毒基因表达失调。这个项目的目标是提高我们对调节EBV潜伏期类型的分子机制的理解。EB病毒是一种重要的人类病原体，与多种恶性肿瘤和淋巴组织增生性疾病有关。EBV可以通过下调免疫原性病毒蛋白来逃避免疫系统检测。更好地了解调节EBV病毒基因表达的分子机制将有助于开发根除EBV潜伏感染的新治疗策略。这项工作将有助于治疗EBV相关的 恶性肿瘤。

DESCRIPTION (provided by applicant): Abstract PI: TEMPERA, ITALO Project: 1K99AI099153-01 Title: Regulation of EBV Latency by Chromosome Conformation Accession Number: 3399731 ================== NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS, THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE. ================== The Epstein-Barr virus is a human gamma herpesvirus that infects B-lymphocytes. The EBV latent infection is associated with several human malignancies, including Burkit's lymphoma (BL) and nasopharyngeal carcinoma (NPC). During latency EBV is able to adopt at least four different gene expression programs that are referred to as latency types. These gene expression programs are regulated by alternative promoter utilization. Since the latency types are differentially immunogenic, the control of viral gene expression and promoter selection is a critical step for EBV to establish a long-term infection. Although progress has been made, the mechanism that regulates EBV gene expresion has not yet been elucidated. The analysis of chromatin surrounding the EBV latent promoters revealed that different epigenetic patterns correspond to different latency types. Moreover, we found that the cellular factor CTCF binds at several key regions of the EBV genome and regulates promoter selection and viral gene expression. We have also proved that CTCF can promote alternative chromatin loops between the viral promoters and the origin of replication of EBV, suggesting that chromatin structure can contribute to regulate EBV latency types. This proposal, combining classical biochemical methodology and chromosome conformation analysis, seeks to reveal the role of three- dimensional architecture of the EBV genome in the regulation of viral gene expression in different latency types. The aim of this study is to use this novel approach to: 1) determine the role of CTCF/Cohesin interaction in the regulation of EBV high-order chromatin structure during latent infection; 2) determine the role of the viral protein EBNA1 in the regulation of EBV genome conformation; 3) determine if EBNA1 promotes inter- chromosomal DNA interactions between virus-host and host-host chromosomes; and 4) test if PARP1 inhibition deregulates the EBV chromosome architecture and viral gene expression. The goal of this project is to improve our understanding of the molecular mechanism that regulates EBV latency types. Public Health Relevance EBV is an important human pathogen that has been linked to multiple malignances and lymphoproliferative disorders. EBV can evade immune system detection by down regulating immunogenic viral proteins. Obtaining a better understanding of the molecular mechanism that regulates EBV viral gene expression will help in the development of new therapeutic strategies for the eradication of EBV latent infection. This work will facilitate the treatment of EBV-related malignancies.