KSHV RTA: more than viral replication

KSHV RTA：不仅仅是病毒复制

• 批准号: 8318065
• 负责人: Jae U Jung
• 金额: $ 32万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318065
• 关键词: Acetylation; Affect; Animal Model; Antibody Formation; Bacterial Artificial Chromosomes; Callithrix jacchus jacchus; Cancer Etiology; Cells; Characteristics; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Circular DNA; Complication; DNA; Deubiquitination; Development; Drug resistance; Epigenetic Process; Event; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genome; Genome Stability; Goals; Grant; HIV Infections; HIV-1; Herpesviridae; Herpesviridae Infections; Heterochromatin; Highly Active Antiretroviral Therapy; Histones; Human; Human Herpesvirus 8; In Vitro; Incidence; Infection; Kaposi Sarcoma; Lesion; Leukocytes; Life; Lymphoma; Lytic; Malignant Neoplasms; Malignant lymphoid neoplasm; Methylation; Modeling; Modification; Multicentric Angiofollicular Lymphoid Hyperplasia; Mus; Nucleosomes; Oral; Outcome; Pathogenesis; Patients; Pattern; Play; Pleural effusion disorder; Polycomb; Post-Translational Protein Processing; Primates; Process; Proteins; Race; Recombinants; Regulation; Research; Role; Route; Stress; Structure; Time; Transcriptional Regulation; Ubiquitination; Viral; Viral Genes; Virus; Virus Latency; arm; bacterial genetics; base; genetic manipulation; genome-wide; histone modification; in vivo; innovation; latent gene expression; lytic gene expression; lytic replication; programs; reactivation from latency; tool; transcription factor; tumor

DESCRIPTION (provided by applicant): Ever since their existence, there has been an everlasting arms race between viruses and their host cells. Host cells have developed numerous strategies to silence viral gene expression, whereas viruses always find ways to overcome these obstacles. Accordingly, viruses have evolved to take full advantage of existing cellular chromatin components to activate or repress its own genes when needed. In fact, host epigenetic modifications of the herpesviral genome chromatin play a key role in the transcriptional control of latent and lytic genes during a productive viral lifecycle. Kaposi's sarcoma-associated herpesvirus (KSHV) is a ubiquitous herpesvirus that establishes a life-long persistent infection in humans and is associated with Kaposi's sarcoma and several lymphoid malignancies. During latency, the KSHV genome persists as a multicopy circular DNA assembled into nucleosomal structures. While viral latency is characterized by restricted viral gene expression, reactivation induces the lytic replication program and the expression of viral genes in a defined sequential and temporal order. Our preliminary study demonstrates that (1) the latent and lytic chromatins of KSHV are associated with a distinctive pattern of activating and repressive histone modifications whose distribution changes upon reactivation in an organized manner in correlation with the temporally ordered expression of viral lytic genes. Furthermore, (2) the evolutionarily conserved Polycomb group proteins and histone deubiquitinases also play a critical role in the regulation of KSHV latency and reactivation by regulating the viral chromatin structure. Thus, the epigenetic program of KSHV is at the crux of restricting latent gene expression and the orderly expression of lytic genes. The goal of this study is to better understand how epigenetic modifications of the KSHV genome affect viral latency and lytic replication, to thereby contribute to the development of a persistent infection and subsequent pathogenic events in vivo. Based on our preliminary studies, we hypothesize that the proper epigenetic regulation of the KSHV genome is critical for viral persistency during latency and reactivation, and for pathogenesis in KSHV infected lesions. This proposal is highly innovative, utilizing well-established comprehensive genome-wide ChIP array, BAC genetics, and in vivo experimental conditions.

描述（由申请人提供）：自从病毒存在以来，它们和宿主细胞之间就一直存在着一场永无止境的军备竞赛。宿主细胞已经发展出许多策略来沉默病毒基因表达，而病毒总是找到克服这些障碍的方法。因此，病毒已经进化到在需要时充分利用现有的细胞染色质成分来激活或抑制自己的基因。事实上，宿主疱疹病毒基因组染色质的表观遗传修饰在病毒生命周期中潜伏和裂解基因的转录控制中起着关键作用。卡波西氏肉瘤相关疱疹病毒（KSHV）是一种普遍存在的疱疹病毒，在人类中建立终身持续性感染，并与卡波西氏肉瘤和几种淋巴样恶性肿瘤有关。在潜伏期，KSHV基因组以多拷贝环状DNA的形式存在，组装成核小体结构。病毒潜伏期的特征是病毒基因的表达受到限制，而再激活则会诱导裂解复制程序和病毒基因的表达，其顺序和时间顺序是确定的。我们的初步研究表明：(1)KSHV的潜伏和裂解染色质与一种独特的激活和抑制组蛋白修饰的模式有关，其分布在重新激活后以有组织的方式发生变化，与病毒裂解基因的时间顺序表达相关。此外，(2)进化上保守的Polycomb蛋白和组蛋白去泛素酶也通过调节病毒染色质结构，在KSHV潜伏期和再激活的调控中发挥关键作用。因此，KSHV的表观遗传程序是制约潜伏基因表达和裂解基因有序表达的关键。本研究的目的是更好地了解KSHV基因组的表观遗传修饰如何影响病毒潜伏期和裂解复制，从而促进体内持续感染和随后的致病事件的发展。基于我们的初步研究，我们假设KSHV基因组的适当表观遗传调控对于病毒在潜伏期和再激活期间的持续性以及KSHV感染病变的发病机制至关重要。该建议具有高度创新性，利用了完善的全基因组芯片阵列、BAC遗传学和体内实验条件。