Epigenetic Regulation of Epstein-Barr Virus

EB 病毒的表观遗传调控

基本信息

批准号：
10363894
负责人：
PAUL M LIEBERMAN
金额：
$ 36.46万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-15 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10363894
关键词：
ATP phosphohydrolase ATRX gene Acquired Immunodeficiency Syndrome Architecture Autoimmunity B lymphocyte immortalization Binding Binding Sites Biological Assay Cell physiology Cells Chromatin Chromatin Modeling Chromosomes Complex Cytosine DAXX gene DNA DNA Methylation Development EBV-associated disease Environment Epigenetic Process Episome Epithelial Epithelial Cells Epstein Barr virus associated oncogenesis Epstein-Barr Virus Infections Epstein-Barr Virus latency Event Funding Gene Expression Gene Expression Profile Gene Expression Regulation Genetic Transcription Genome Goals HIV Histone H3 Histones Human Human Herpesvirus 4 Infection Latent virus infection phase Lymphoid Cell Malignant Neoplasms Malignant lymphoid neoplasm MicroRNAs Molecular Chaperones Molecular Conformation Mutation Nature Nucleosomes Oncogenes Oncogenic Oral Oxides PAX5 gene Pathogenesis Pathway interactions Patients Phase Phenotype Positioning Attribute Process Proteins Role Testing Therapeutic Intervention Transcriptional Regulation Viral Viral Genes Viral Genome Viral Oncogene Virus Latency carcinogenesis cell type cohesin demethylation epigenetic regulation epigenome gammaherpesvirus histone modification latent infection methylation pattern novel therapeutics prevent programs promoter tool transcription factor tumor tumorigenesis virus related cancer

项目摘要

The long-term goal of this R01 is to understand how epigenetic mechanisms control Epstein-Barr Virus (EBV) latency and carcinogenesis. EBV latent infection is associated with a diverse spectrum of epithelial and lymphoid malignancies. The highly adaptive nature of EBV infection to various host cells and environments suggests that it exploits fundamental cellular processes of dynamic gene regulation. EBV is known to adapt various gene expression programs, termed latency types, in different host cell and tumor environments. These latency types and viral gene expression patterns are determined by epigenetic factors ranging from nucleosome positioning, histone modifications, CpG DNA methylation, transcription factor occupancy, and chromosome conformation. The mechanisms regulating viral and host DNA epigenetic controls are not fully understood but are critical for understanding viral latency and oncogenesis in diverse cell types. We have been investigating the process through which EBV establishes and regulates the epigenetic program of both viral and host genomes. In the previous funding cycles, we identified the viral tegument protein BNRF1 as a binding partner of DAXX-histone H3.3 complex and showed that this interaction is required for viral chromatin assembly and gene expression during the early, pre-latent phase of infection. We have identified viral and cellular transcription factor binding sites for EBNA1, EBNA2, CTCF, cohesin (RAD21), EBF1, RBP JK and chromosome conformations that change during the establishment of latency and correlate with different latency types. We have assayed chromatin accessibility and RNA expression changes during the multiple stages of EBV-induced B-cell immortalization to correlate gene expression with chromatin architecture. We have also found that viral and host DNA methylation programming depends on viral EBNA2 and vmiRNAs that coordinately regulate TET2 expression and cytosine hydroxymethylation and demethylation. We now propose to further advance these studies to better understand the role of epigenetic mechanisms in the control of EBV latency and oncogenicity. We will test the overarching hypothesis that EBV reprograms host epigenetic mechanisms to enable viral genome persistence and transcriptional plasticity that drives EBV-associated oncogenesis.

R01 的长期目标是了解表观遗传机制如何控制 Epstein-Barr 病毒 (EBV) 潜伏期和致癌作用。 EBV 潜伏感染与多种上皮和淋巴恶性肿瘤相关。 EBV 感染对各种宿主细胞和环境的高度适应性表明它利用了动态基因调控的基本细胞过程。已知 EBV 在不同的宿主细胞和肿瘤环境中适应各种基因表达程序，称为潜伏类型。这些潜伏类型和病毒基因表达模式由核小体定位、组蛋白修饰、CpG DNA 甲基化、转录因子占据和染色体构象等表观遗传因素决定。调节病毒和宿主 DNA 表观遗传控制的机制尚未完全了解，但对于了解不同细胞类型中的病毒潜伏期和肿瘤发生至关重要。我们一直在研究 EBV 建立和调节病毒和宿主基因组表观遗传程序的过程。在之前的资助周期中，我们确定了病毒外皮蛋白 BNRF1 作为 DAXX-组蛋白 H3.3 复合物的结合伴侣，并表明这种相互作用是感染早期、潜伏期前病毒染色质组装和基因表达所必需的。我们已经确定了 EBNA1、EBNA2、CTCF、粘连蛋白 (RAD21)、EBF1、RBP JK 和染色体构象的病毒和细胞转录因子结合位点，这些位点在潜伏期建立过程中发生变化，并与不同的潜伏期类型相关。我们分析了 EBV 诱导的 B 细胞永生化的多个阶段中染色质可及性和 RNA 表达的变化，以将基因表达与染色质结构相关联。我们还发现，病毒和宿主 DNA 甲基化编程依赖于病毒 EBNA2 和 vmiRNA，它们协调调节 TET2 表达以及胞嘧啶羟甲基化和去甲基化。我们现在建议进一步推进这些研究，以更好地了解表观遗传机制在控制 EBV 潜伏期和致癌性中的作用。我们将测试这一总体假设，即 EBV 重新编程宿主表观遗传机制，以实现病毒基因组持久性和转录可塑性，从而驱动 EBV 相关的肿瘤发生。