Epigenetic Regulation of Epstein-Barr Virus

EB 病毒的表观遗传调控

基本信息

批准号：
9415988
负责人：
PAUL M LIEBERMAN
金额：
$ 46.9万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9415988
关键词：
ATRX gene Acquired Immunodeficiency Syndrome Antiviral Agents Architecture B Cell Proliferation B-Lymphocytes Binding Binding Sites Biochemical Genetics Cell Differentiation process Cells Cellular biology Chromatin Chromatin Loop Chromatin Modeling Chromosomes Competence Complex DNA DNA biosynthesis Development Elements Enhancers Environment Epigenetic Process Episome Epithelial Epithelial Cells Epstein-Barr Virus Infections Epstein-Barr Virus latency Event Evolution Family Gene Expression Genetic Transcription Genomics HIV Heterochromatin Histone H3 Histones Human Human Herpesvirus 4 Investigation LMP1 Latent virus infection phase Life Lymphoid Lymphoid Cell Malignant Neoplasms Methods Modification Molecular Molecular Chaperones Molecular Conformation Oncogenes Oncogenic Viruses Oral Pathogenesis Patients Pattern Phase Play Point Mutation Post-Translational Protein Processing Primary Infection Proteins Purines Resolution Role Specific qualifier value Stress Structure Testing Viral Viral Genes Viral Genome Virus antiviral immunity cancer cell carcinogenesis cell type cohesin epigenetic regulation epigenome gammaherpesvirus histone modification insight latent infection member next generation novel therapeutics prevent programs promoter public health relevance transcription factor tumor virus genetics

项目摘要

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is a ubiquitous human gamma-herpesvirus that establishes life-long latency in B- lymphocytes. EBV is also a causative agent of diverse lymphoid and epithelial malignancies. The variety of EBV tumor types can be partly attributed to a plasticity of viral gene expression and DNA replication programs. These different gene expression programs allow the virus to adapt to a wide range of host cell types and differentiation states, to survive environmental stress conditions and evade host innate and adaptive antiviral immunity. How EBV genomes establish stable latent infections capable of adapting to various host environments, and how this promotes cancer cell evolution remains an important, unanswered question. In this proposal, we will test the hypothesis that EBV gene expression and replication programs are coordinately regulated with host cell information through complex epigenetic mechanisms. The assembly of chromatin and the patterning of histone post-translational modifications is an early event in the establishment of latent infection and determining the transcriptional competence of the viral genome. We will continue ongoing investigations into the mechanism of viral chromatin assembly during primary infection. Aim 1 will focus on the interaction of the viral tegument protein BNRF1 with cellular histone chaperone and intrinsic anti-viral factors Daxx-ATRX to generate latent episomes competent for transcription. Aim 2 will investigate how the viral chromatin is organized by architectural factors CTCF and cohesins, that facilitate functional interactions between promoters and enhancers to regulate viral gene expression. We will also determine how CTCF prevents epigenetic drift between chromosome domains. Finally, Aim 3 will determine how viral and host master-regulatory transcription factors function cooperatively with chromatin organizing factors and epigenetic modifiers to establish dynamic gene expression programs that are responsive to changes in host cell conditions, including those associated with carcinogenesis. We will use next-generation genomic methods to investigate how the viral epigenome is configured in different latency types. We will use high-resolution chromosome conformation methods to investigate DNA regulatory interactions that may determine viral gene expression programs. We will also use biochemical and viral genetic methods to experimentally validate and test the mechanistic basis for epigenetic control. The studies will provide important new information on how EBV gene expression programs are coordinated with host-cell biology, and also provide new insights into the epigenetic control of viral genes associated with EBV carcinogenesis.

描述（由申请人提供）：EB病毒（EBV）是一种普遍存在的人类γ-疱疹病毒，其在B淋巴细胞中建立终生潜伏期，也是多种淋巴和上皮恶性肿瘤的病原体。病毒的不同类型可部分归因于病毒基因表达和DNA复制程序的可塑性，这些不同的基因表达程序使病毒能够适应多种宿主细胞类型和分化。指出，为了在环境应激条件下生存并逃避宿主先天性和适应性抗病毒免疫，EBV 基因组如何建立能够适应各种宿主环境的稳定的潜伏感染，以及这如何促进癌细胞进化仍然是一个重要的、尚未解答的问题。将检验以下假设：EBV 基因表达和复制程序通过复杂的表观遗传机制与宿主细胞信息协调调节。染色质的组装和组蛋白翻译后修饰的模式是建立的早期事件。潜伏感染并确定病毒基因组的转录能力。目标 1 将重点研究病毒外皮蛋白 BNRF1 与细胞组蛋白伴侣和内在抗病毒因子 Daxx 的相互作用。 -ATRX 生成能够转录的潜在附加体，目标 2 将研究病毒染色质如何通过结构因子 CTCF 和粘连蛋白进行组织，从而促进启动子和增强子之间的功能相互作用。我们还将确定 CTCF 如何防止染色体结构域之间的表观遗传漂变，最后，目标 3 将确定病毒和宿主主调控转录因子如何与染色质组织因子和表观遗传修饰因子协同发挥作用，以建立动态基因表达程序。对宿主细胞条件的变化做出反应，包括与致癌相关的变化。我们将使用下一代基因组方法来研究病毒表观基因组在不同潜伏类型中的配置。我们将使用高分辨率染色体构象方法来研究 DNA 调控。我们还将使用生物化学和病毒遗传学方法来实验验证和测试表观遗传控制的机制基础，这些研究将为 EBV 基因表达程序如何与宿主细胞生物学协调提供重要的新信息。，也为与 EBV 致癌相关的病毒基因的表观遗传控制提供了新的见解。