Epstein-Barr Virus Nuclear Protein B Cell Growth Transformation

EB病毒与免疫抑制和HIV感染者的Burkitt‘s淋巴瘤、Hodgkin’s淋巴瘤和淋巴增殖性疾病有因果关系。在T细胞免疫反应不足的人中，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，静止的B淋巴细胞转化为持续增殖的淋巴母细胞(LCLS)，是一种与EBV致癌相关的实验有用的模型。EBNA3A和EBNA3C是LCL生长所必需的，它们调控着数百个细胞基因的表达。EBNA3A和EBNA3C与数千个增强子结合，改变增强子-启动子循环。EBNA3A和3C抑制CDKN2A/B p16INK4A和p14ARF的表达，使细胞持续增殖。为了进一步研究EBNA3A和EBNA3C调控转录的分子机制，我们的具体目标是：1.利用Hi-C和CHIA-PET检测EBNA3A/3C对基因组重组的影响及其对LCL生长的影响。2.通过检测EBNA3A/3C对CDKN2A/B位点增强子/沉默子启动子循环的影响，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如何在EBV介导的增长转化中做出贡献提供新的见解。

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.