KSHV Latency Regulation

KSHV 延迟调节

• 批准号: 10412663
• 负责人: Kenneth M Kaye
• 金额: $ 71.17万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-05 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412663
• 关键词: ASH2L gene; Acquired Immunodeficiency Syndrome; Africa South of the Sahara; Binding; Biochemical; Biology; Cell Nucleus; Cell Survival; Cell division; Cells; ChIP-seq; Childhood Leukemia; Chromatin; Chromosomes; Complex; Crystallization; DNA biosynthesis; Daughter; Deposition; Development; Epidemic; Epigenetic Process; Episome; Etiology; Family; Gene Expression; Genes; Genetic; Genome; Herpesviridae; Herpesviridae Infections; Histone H3; Human; Human Herpesvirus 8; Immunocompromised Host; Individual; Infection; Kaposi Sarcoma; Knockout Mice; Link; Lysine; Lytic; Maintenance; Malignant Neoplasms; Mammals; Mediating; Methylation; Mitosis; Mixed-Lineage Leukemia; Modification; Multicentric Angiofollicular Lymphoid Hyperplasia; Mus; N-terminal; Oral cavity; Organ; Proliferating; Proteins; Regulation; Role; SET Domain; Saliva; Site; Structure; Transcriptional Regulation; Viral; Viral Genes; Viral Genome; Viral Proteins; Virus; Virus Diseases; Virus Latency; Visceral; Work; adult leukemia; daughter cell; experimental study; gammaherpesvirus; histone methylation; histone methyltransferase; in vivo; insight; latency-associated nuclear antigen; neoplastic cell; novel; prevent; primary effusion lymphoma; promoter; recruit; segregation; transcriptome sequencing; transmission process; tumor

Kaposi's sarcoma (KS) herpesvirus (KSHV) is the causative agent of KS and primary effusion lymphoma (PEL), and is tightly linked with multicentric Castleman's disease (MCD). These tumors occur most commonly in immunocompromised individuals, especially those with AIDS. There are no specific therapies for these malignancies. KS is the leading AIDS malignancy, and is epidemic in sub Saharan Africa. KS commonly involves the oral cavity and can disseminate to visceral organs. Saliva is the vehicle of transmission for KSHV. Latency is the hallmark of KSHV and gammaherpesvirus infection. KSHV latently infects cells, including tumor cells, and viral genomes persist as extrachromosomal, circularized, multi-copy, episomes. To persist in proliferating cells, viral episomes must replicate, and following mitosis, segregate to daughter cell nuclei. Tumor cell viability is dependent on latent KSHV infection. The latency-associated nuclear antigen (LANA) is one of several viral genes expressed in latency. LANA mediates KSHV episome maintenance, and is necessary and sufficient for episome persistence in the absence of other viral genes. In addition to episome persistence, LANA exerts important roles in transcriptional regulation. Epigenetic histone H3 lysine 4 (H3K4) tri-methylation (H3K4me3) marks are associated with actively transcribed genes and are deposited by histone methyltransferase (HMT) complexes. There are six HMTs (MLL1-4, Set1A/B) in mammals responsible for catalyzing methylation of histone H3 at K4 through a SET domain. LANA is highly enriched at H3K4me3 peaks at both viral and host chromatin, yet the mechanism of LANA recruitment to and its function at these sites remains unclear. We have discovered novel LANA interactions with HMT components and that LANA regulates specific HMT activity. Further, we find this HMT activity is critical for virus latency establishment. This work will use rigorous, detailed, in depth approaches to investigate the mechanistic basis of these findings. Experiments will investigate the role of the HMT activity in LANA mediated episome persistence. We will investigate the role of the LANA-HMT interaction in LANA and HMT chromatin targeting of virus and host, and its effects on H3K4me3 deposition and gene expression. Experiments will also investigate the mechanism of LANA’s regulation of HMT activity and its role in virus latency. LANA and HMT activity are critical for latency, and this work therefore provides novel and important insight into a fundamental component of KSHV biology.

卡波西肉瘤（KS）疱疹病毒（KSHV）是KS和原发性渗出液的病原体 淋巴瘤（PEL），并且与多中心Castleman病（MCD）紧密相关。这些肿瘤大多发生在 常见于免疫功能低下的个体，尤其是艾滋病患者。没有具体的治疗方法 这些恶性肿瘤KS是主要的艾滋病恶性肿瘤，并且在撒哈拉以南非洲流行。一般来说， 累及口腔并可扩散至内脏器官。唾液是KSHV的传播媒介。 潜伏期是KSHV和γ疱疹病毒感染的标志。KSHV潜伏感染细胞，包括 肿瘤细胞和病毒基因组作为染色体外的、环状的、多拷贝的附加体持续存在。坚持 在增殖的细胞中，病毒游离体必须复制，并且在有丝分裂后，分离到子细胞核。 肿瘤细胞活力依赖于潜伏的KSHV感染。 潜伏相关核抗原（拉娜）是潜伏期表达的几种病毒基因之一。 拉娜介导KSHV附加体的维持，并且是附加体在细胞中持续存在的必要和充分条件。 没有其他病毒基因。除了附加体持久性，拉娜在转录调控中发挥重要作用， 调控 表观遗传组蛋白H3赖氨酸4（H3 K4）三甲基化（H3 K4 me 3）标记与活性相关。 转录的基因，并通过组蛋白甲基转移酶（HMT）复合物沉积。有六个HMT （MLL 1 -4，Set 1A/B）在哺乳动物中负责通过SET催化组蛋白H3在K4处的甲基化 域拉娜在病毒和宿主染色质的H3 K4 me 3峰处高度富集，但LANA的机制是， 拉娜在这些位点的招募及其功能尚不清楚。 我们已经发现了新的拉娜与HMT组分的相互作用，并且拉娜调节HMT的特异性表达。 HMT活性。此外，我们发现这种HMT活性对病毒潜伏期的建立至关重要。这项工作将使用 严格的，详细的，深入的方法来调查这些发现的机制基础。实验将 研究HMT活性在拉娜介导的附加体持久性中的作用。我们将研究 拉娜和HMT染色质靶向病毒和宿主中LANA-HMT相互作用及其对 H3 K4 me 3沉积和基因表达。实验还将研究拉娜的机制 HMT活性的调节及其在病毒潜伏期中的作用。拉娜和HMT活动对延迟至关重要， 因此，这项工作为KSHV生物学的基本组成部分提供了新的和重要的见解。