REGULATION OF EBV TRANSCRIPTION IN BURKITT'S LYMPHOMA

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。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，包括地方性伯基特、S淋巴瘤和鼻咽癌。这项研究的主要目的是了解在限制性病毒潜伏期(组1或组2潜伏期)期间EBF基因表达的调节，观察到在免疫功能良好的个体中出现的EBV相关肿瘤。具体地说，在EBV潜伏期的生长转化形式(组3潜伏期)中表达的6种EB病毒核抗原(EBNAs)中，只有EBNA1在限制性病毒潜伏期表达。EBNA1对维持病毒Episome是必不可少的，而且最近被证明是对MHC I类递呈的屈光。因此，EBNA1的表达不会导致宿主免疫反应识别肿瘤细胞。最近对健康血清阳性个体的长期储存库的表征表明，EBV存在于记忆B细胞中，其中病毒基因表达最少，这表明有限形式的病毒潜伏期也可能参与体内的持久性。我们已经确定了一个独特的病毒启动子QP，它参与了在限制性病毒潜伏期内推动EBNA1基因的排除表达；鉴定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；确定在限制性病毒潜伏期或第3组潜伏期期间QP周围的区域保持低甲基化；并定位了参与调节QP活性的关键顺式元件，包括鉴定和鉴定转录起始点附近的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.