Regulation of EBV Transcription in Burkitt's Lymphoma

伯基特淋巴瘤中 EBV 转录的调控

• 批准号: 7233629
• 负责人: SAMUEL H SPECK
• 金额: $ 27.24万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7233629
• 关键词: Appendix; Automobile Driving; B-Lymphocytes; Burkitt Lymphoma; Cells; Chronic; CpG dinucleotide; DNA Methylation; DNA Modification Methylases; Development; Dinucleoside Phosphates; Epstein-Barr Virus Infections; Gene Expression; Genes; Genetic Transcription; Genome; Grant; Growth; Herpesviridae; Human Herpesvirus 4; Immunocompetent; Individual; Infection; Life Cycle Stages; Mammalian Cell; Maps; Memory B-Lymphocyte; Methylation; Methyltransferase; Modeling; Mus; Mutation; Pattern; Personal Communication; Play; Recombinants; Regulation; Reporting; Role; Simplexvirus; Specificity; Structure of germinal center of lymph node; Title; Viral; Viral Genome; Viral Proteins; Virus; Virus Latency; in vivo; infected B cell; insight; programs; promoter; tumor

DESCRIPTION (provided by applicant): This proposal focuses on regulation of y-herpesvirus latency-associated gene expression in the long-term latency reservoir(s). We have recently shown that murine gammaherpesvirus 68 (yHV68), like EBV, persists within memory B cells. In EBV latently infected memory B cells, there is very limited viral gene expression. In contrast, EBV infection of naive and geminal center B cells leads to expression of a panel of latency-associated genes whose products play a pivotal role in driving differentiation of these virus infected B cells into the memory B cell reservoir. We hypothesize that yHV68 infection of naive B cells also leads to their differentiation into geminal center and memory B cells. We further hypothesize that this differentiation is accompanied by changes in the viral latency-associated gene expression. Importantly, we and others have consistently shown a tight correlation between methylation of the EBV genome and establishment of restricted viral latency programs. The under-representation of CpG dinucleotides in the EBV and yHV68 genomes is evidence that methylation of these viral genomes is a normal part of their life cycle in the infected host. The parallels between EBV and yHV68 latency in vivo justify the proposed characterization of the role of DNA methylation in regulating chronic yHV68 infection in mice. Importantly, EBV genome methylation is a hallmark of all characterized EBV-associated tumors that arise in immunocompetent hosts. The latter provides further impetus to understand the underlying mechanisms involved in, and the relationship between, methylation of y-herpesvirus genomes and chronic infection. Aim 1. Analysis of EBV restricted latency analyze EBNA1 gene transcription from Qp; assess specificity/targeting of Cp/Wp methylation; Aim 2. Characterization of yHV68 latency programs characterize latency-associated gene transcription in distinct latency reservoirs; develop yHV68 latency models; map latency-associated viral promoters; Aim 3. Investigate role of methylation in regulating yHV68 latency-associated gene expression analyze viral genome methylation in naive and memory B cell reservoirs; characterize expression of de novo methyltransferases in B cells; develop recombinant yHV68 that inhibit Dnmt3a/3b expression.

描述（由申请人提供）：该提案的重点是在长期潜伏期储层中对与潜伏期相关的基因表达的调节。我们最近表明，像EBV一样，鼠γγ病毒68（YHV68）一直存在于记忆B细胞中。在EBV潜在感染的记忆B细胞中，病毒基因表达非常有限。相比之下，幼稚和宝石中心B细胞的EBV感染导致了一组潜伏相关基因的表达，其产物在将这些病毒感染的B细胞分化到记忆B细胞储存中起着关键作用。我们假设YHV68幼稚B细胞的感染也导致它们分化为Geminal Center和Memory B细胞。我们进一步假设这种分化伴随着病毒潜伏相关基因表达的变化。重要的是，我们和其他人始终显示出EBV基因组的甲基化与建立受限制的病毒潜伏期计划之间存在密切的相关性。 EBV和YHV68基因组中CpG二核苷酸的代表性不足是证据表明，这些病毒基因组的甲基化是其在受感染宿主中生命周期的正常部分。体内EBV和YHV68潜伏期之间的相似之处证明了DNA甲基化在调节小鼠中慢性YHV68感染中的作用的提出的表征。重要的是，EBV基因组甲基化是所有与EBV相关的肿瘤的标志，这些肿瘤在免疫能力的宿主中产生。后者提供了进一步的动力，以了解Y HERPESVIRUS基因组和慢性感染的甲基化涉及的潜在机制以及甲基化之间的关系。目标1。分析EBV限制延迟分析QP的EBNA1基因转录；评估CP/WP甲基化的特异性/靶向；目标2。YHV68延迟程序的表征表征了与延迟相关的基因转录在不同的延迟储层中；开发YHV68延迟模型；地图与潜伏期相关的病毒启动子； AIM 3。研究甲基化在调节YHV68潜伏相关的基因表达中的作用，分析了幼稚和记忆B细胞库中病毒基因组甲基化；表征从B细胞中新甲基转移酶的表达；开发抑制DNMT3A/3B表达的重组YHV68。