Epstein-Barr Virus Nuclear Protein B Cell Growth Transformation

Epstein-Barr 病毒核蛋白 B 细胞生长转化

• 批准号: 9977926
• 负责人: Bo Zhao
• 金额: $ 53.25万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-06-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977926
• 关键词: 3-Dimensional; Acquired Immunodeficiency Syndrome; B-Cell Lymphomas; B-Lymphocytes; Binding; Biochemical; Burkitt Lymphoma; CDKN2A gene; Cancer Etiology; Cell Proliferation; Cells; Cessation of life; ChIP-seq; Chromatin Interaction Analysis by Paired-End Tag Sequencing; Chromatin Loop; Complex; DNA; DNA Binding; Data; Enhancers; Enzymes; Epstein Barr Nuclear Antigen 3; Epstein-Barr Virus Infections; Epstein-Barr Virus Nuclear Antigens; Epstein-Barr Virus-Related Malignant Neoplasm; Gene Expression; Genes; Genetic Models; Genetic Transcription; Genome; Growth; HIV; Histones; Hodgkin Disease; Human; Human Herpesvirus 4; IRF4 gene; Immune; Immune response; Immunologic Surveillance; In Vitro; Infection; Intervention; Investigation; Lead; Lymphocyte; Lymphoma; Lymphoproliferative Disorders; Malignant - descriptor; Maps; Mediating; Membrane Proteins; Modeling; Molecular; Nuclear Protein; Polycomb; Process; Proliferating; Proteins; Proteomics; Publishing; RUNX3 gene; Repression; Response Latencies; Rest; SPI1 gene; Site; T-Lymphocyte; Time; Transcription Repressor; Viral Proteins; Virus; antiretroviral therapy; cell growth; chromosome conformation capture; cohesin; genome-wide; in vivo; infected B cell; insight; lymphoblast; lymphoblastoid cell line; novel therapeutics; programs; promoter; recruit; senescence; tumorigenesis

Epstein Barr Virus (EBV) is causally related to Burkitt's Lymphoma, Hodgkin's Lymphoma, and Lymphoproliferative Diseases in immune suppressed and HIV infected people. In humans deficient in T cell immune responses, Latency III infected B-cells can be highly malignant. EBV conversion of Resting B Lymphocytes to continuously proliferating Lymphoblasts (LCLs) by expressing Latency III EBV nuclear antigens EBNA2, LP, 3A, 3C, and Latent Membrane Protein LMP1, is a relevant and experimentally useful model for EBV oncogenesis. EBNA3A and EBNA3C are essential for LCL growth and they regulate the expression of hundreds of cell genes. EBNA3A and EBNA3C bind to thousands of enhancer sites and alter enhancer-promoter looping. EBNA3A and 3C suppress CDKN2A/B p16INK4A and p14ARF expression to enable continuous cell proliferation. To further characterize the molecular mechanisms through which EBNA3A and EBNA3C regulate transcription, our specific aims are to: 1. Determine the effect of EBNA3A/3C on genome reorganization and their effect on LCL growth using Hi-C and ChIA-PET. 2. Determine the mechanisms through which EBNA3A/3C suppress senescence by examining the effect of EBNA3A/3C on enhancer/silencer promoter looping at the CDKN2A/B loci. 3. Determine the molecular mechanisms by which EBNA3A/C are tethered to DNA. These studies will provide new insights on how EBNA3A and EBNA3C contribute to EBV mediated growth transformation.

EB 病毒 (EBV) 与免疫抑制和 HIV 感染者的伯基特淋巴瘤、霍奇金淋巴瘤和淋巴增殖性疾病有因果关系。在缺乏 T 细胞免疫反应的人类中，潜伏期 III 感染的 B 细胞可能是高度恶性的。通过表达潜伏期 III EBV 核抗原 EBNA2、LP、3A、3C 和潜伏膜蛋白 LMP1，将静息 B 淋巴细胞 EBV 转化为持续增殖的淋巴细胞 (LCL)，是 EBV 肿瘤发生的相关且实验上有用的模型。 EBNA3A 和 EBNA3C 对于 LCL 生长至关重要，它们调节数百种细胞基因的表达。 EBNA3A 和 EBNA3C 与数千个增强子位点结合并改变增强子-启动子环。 EBNA3A 和 3C 抑制 CDKN2A/B p16INK4A 和 p14ARF 表达，从而实现细胞持续增殖。为了进一步表征 EBNA3A 和 EBNA3C 调节转录的分子机制，我们的具体目标是： 1. 使用 Hi-C 和 ChIA-PET 确定 EBNA3A/3C 对基因组重组的影响及其对 LCL 生长的影响。 2. 通过检查 EBNA3A/3C 对 CDKN2A/B 基因座增强子/沉默子启动子环的影响，确定 EBNA3A/3C 抑制衰老的机制。 3. 确定 EBNA3A/C 与 DNA 结合的分子机制。这些研究将为 EBNA3A 和 EBNA3C 如何促进 EBV 介导的生长转化提供新的见解。