REGULATION OF EBV TRANSCRIPTION IN BURKITT'S LYMPHOMA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。爱泼斯坦-巴尔病毒感染与几种人类恶性肿瘤的发展密切相关，包括地方性的伯基特病。S淋巴瘤和鼻咽癌。本研究的主要目的是了解EBF基因在限制性病毒潜伏期（1组或2组潜伏期）期间的表达调控，在免疫能力强的个体中观察到ebv相关肿瘤。具体来说，在EBV潜伏期（第3组潜伏期）的生长转化形式中表达的6种ebna中，只有EBNA1在限制性病毒潜伏期中表达。EBNA1对病毒片段的维持至关重要，最近的研究表明，EBNA1对MHC i类的呈递具有折射性，因此，EBNA1的表达不会导致宿主免疫应答对肿瘤细胞的识别。最近对健康血清阳性个体的长期库的表征表明，EBV存在于病毒基因表达最少的记忆B细胞群体中，这表明病毒潜伏期的限制形式也可能参与体内持久性。我们已经确定了一个独特的病毒启动子，Qp，参与在限制病毒潜伏期驱动EBNA1基因的排斥表达；表征了病毒基因组的甲基化，并观察到EBNA基因启动子Cp和Wp（在第3组潜伏期期间活跃）的甲基化与限制性病毒潜伏期的建立密切相关；确定Qp周围区域在受限病毒潜伏期或3组潜伏期期间保持低甲基化；并绘制了参与调节Qp活性的关键顺式元件，包括鉴定和表征转录起始位点附近的IRF1/IRF2位点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Epstein-Barr virus infection is closely associated with the development of several human malignancies, including the endemic form of Burkitt?s lymphoma and nasopharyngeal carcinoma. The major goal of this research is to understand the regulation of EBF gene expression during restricted viral latency (group 1 or group 2 latency), observed in the EBV-associated tumors that arise in immunocompetent individuals. Specifically, of the six Epstein-Barr nuclear antigens (EBNAs) expressed during the growth transforming form of EBV latency (group 3 latency), only EBNA1 is expressed during restricted viral latency. EBNA1 is essential for maintenance of the viral episome, and has recently been shown to be refractile to presentation by MHC class I. Thus, expression of EBNA1 does not lead to recognition of tumor cells by the host immune response. Recent characterization of the long term reservoir in healthy seropositive individuals indicates that EBV is present in a population of memory B cells in which there is minimal viral gene expression, suggesting that a restricted form of viral latency may also be involved in persistence in vivo. We have identified a distinct viral promoter, Qp, involved in driving exclusing expression of the EBNA1 gene during restricted viral latency; characterized methylation of the viral genome and observed a tight correlation between methylation of the EBNA gene promoters Cp and Wp (active during group 3 latency) and establishment of restricted viral latency; determined that the region around Qp remains hypomethylaed during either restricted viral latency or group 3 latency; and mapped critical cis-elements involved in regulating Qp activity, including identification and characterization of an IRF1/IRF2 site adjacent to the site of transcription initiation.