Epstein-Barr Virus Nuclear Protein B Cell Growth Transformation

爱泼斯坦巴尔病毒（EBV）与免疫抑制和HIV感染者中的伯基特淋巴瘤、霍奇金淋巴瘤和恶性增殖性疾病有因果关系。在缺乏T细胞免疫应答的人类中，潜伏期III感染的B细胞可能是高度恶性的。通过表达潜伏III期EBV核抗原EBNA 2、LP、3A、3C和潜伏膜蛋白LMP 1，静止B淋巴细胞向持续增殖的淋巴母细胞（LCL）的EBV转化是EBV肿瘤发生的相关和实验上有用的模型。EBNA 3A和EBNA 3C是LCL生长所必需的，它们调节数百个细胞基因的表达。EBNA 3A和EBNA 3C与数千个增强子位点结合并改变增强子-启动子环。EBNA 3A和3C抑制CDKN 2A/B p16 INK 4A和p14 ARF表达，以使细胞持续增殖。为了进一步表征EBNA 3A和EBNA 3C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EBNA 3A/3C对基因组重组的影响及其对LCL生长的影响。2.通过检测EBNA 3A/3C对CDKN 2 A/B基因座上增强子/沉默子启动子环的影响，确定EBNA 3A/3C抑制衰老的机制。3.确定EBNA 3A/C与DNA结合的分子机制。这些研究将为EBNA 3A和EBNA 3C如何促进EBV介导的生长转化提供新的见解。

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.