Coactivators Regulating EBV Lytic Transcription

调节 EBV 裂解转录的共激活剂

• 批准号: 6754546
• 负责人: PAUL M LIEBERMAN
• 金额: $ 26.54万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6754546
• 关键词: DNA footprinting; Epstein Barr virus; Herpesviridae disease; acyltransferase; chromatin; enzyme activity; gene induction /repression; genetic promoter element; host organism interaction; immunoprecipitation; microorganism culture; nucleosomes; regulatory gene; transcription factor; viral carcinogenesis; virus genetics; virus infection mechanism; virus protein

DESCRIPTION (provided by applicant): Regulation of EBV lytic cycle gene expression may have important and underappreciated clinical significance for EBV-related malignancies and diseases. EBV establishes a latent infection in B-lymphocytes that can be disrupted by transcriptional activation of the viral immediate early genes BZLF1 (Zta) and BRLF1 (Rta). The EBV genome exists as a nucleosomal episome during latency, and histone deacetylase inhibitors are potent stimulators of viral lytic gene expression. Reactivation correlates with histone hyperacetylation at the Zta and Rta promoters, further indicating the importance of chromatin modification in controlling the switch from latent to lytic transcription. In this application, we propose to test the hypothesis that EBV reactivation is regulated by chromatin modifications. Our preliminary data suggests that the Zta promoter is actively repressed by a histone deacetylase (HDAC)-associated corepressor that can be relieved by CBP/p300 histone acetylase (HAT) activity. Specific aim 1 will investigate the regulation of the Zta promoter by chromatin modification and remodeling. We have also found that CBP potentiates Zta transcription activation in a complex and promoter-dependent manner. Specific aim 2 will investigate the mechanisms of CBP transcriptional coactivation of Zta. Finally, we have found that Zta stimulates the nucleosome-specific HAT activity of CBP by a mechanism that we believe is novel and highly significant. Specific aim 3 explores the biochemical basis and biological significance of Zta mediated stimulation of CBP HAT activity. These aims should provide information important for EBV regulation of lytic cycle gene expression, in particular, and for eukaryotic transcription regulation, in general.

描述（由申请人提供）：EBV裂解周期基因的调节 表达可能具有重要且低估的临床意义 与EBV相关的恶性肿瘤和疾病。 EBV在 B淋巴细胞可能会因病毒的转录激活而破坏 直接的早期基因BZLF1（ZTA）和BRLF1（RTA）。 EBV基因组作为一个 潜伏期和组蛋白脱乙酰基酶抑制剂期间的核小体偶发组是 病毒裂解基因表达的有效刺激剂。重新激活与 ZTA和RTA启动子的组蛋白高乙酰化，进一步表明 染色质修饰在控制从潜在到的开关中的重要性 裂解转录。在此应用中，我们建议检验假设 EBV重新激活受染色质修饰调节。我们的初步 数据表明ZTA启动子被组蛋白积极抑制 脱乙酰基酶（HDAC）相关的Corepressor可以通过CBP/P300缓解 组蛋白乙酰酶（HAT）活性。特定目标1将调查 通过染色质修饰和重塑对ZTA启动子进行调节。我们 还发现CBP在复合物中增强了ZTA转录激活 和促进者依赖性方式。特定目标2将研究机制 ZTA的CBP转录共激活。最后，我们发现ZTA 通过我们的机制刺激CBP的核小体特异性HAT活性 相信是新颖的，而且非常重要。特定目标3探索 ZTA介导的刺激的生化基础和生物学意义 CBP帽子活动。这些目标应为EBV提供重要的信息 尤其是裂解周期基因表达的调节，对于真核生物 通常，转录调节。