REGULATION OF EBV TRANSCRIPTION IN BURKITT'S LYMPHOMA

伯基特淋巴瘤中 EBV 转录的调控

• 批准号: 7349162
• 负责人: SAMUEL H SPECK
• 金额: $ 4.01万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-09 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349162
• 关键词: gene expression; latent virus infection; lymphoma; methylation; neoplasm /cancer

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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。EB病毒感染与几种人类恶性肿瘤的发生密切相关，包括地方性伯基特？S淋巴瘤和鼻咽癌。本研究的主要目标是了解在免疫活性个体中出现的EBV相关肿瘤中观察到的限制性病毒潜伏期（第1组或第2组潜伏期）期间EBF基因表达的调节。具体地，在EBV潜伏期的生长转化形式（第3组潜伏期）期间表达的六种EB核抗原（EBNA）中，仅EBNA 1在限制性病毒潜伏期期间表达。EBNA 1对于维持病毒附加体是必需的，并且最近已显示对通过MHC I类呈递是无活性的。因此，EBNA 1的表达不会导致宿主免疫应答识别肿瘤细胞。最近对健康血清反应阳性个体中的长期储存库的表征表明，EBV存在于记忆B细胞群体中，其中存在最小的病毒基因表达，这表明病毒潜伏期的限制形式也可能涉及体内持久性。我们已经鉴定了一个独特的病毒启动子Qp，其参与在有限的病毒潜伏期期间驱动EBNA 1基因的排除性表达;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的甲基化之间的紧密相关性（在第3组潜伏期期间活跃）和建立限制性病毒潜伏期;确定Qp周围的区域在限制性病毒潜伏期或组3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，包括鉴定和表征与转录起始位点相邻的IRF 1/IRF 2位点。