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.

Kaposi的肉瘤（KS）疱疹病毒（KSHV）是KS和主要积液的病因 淋巴瘤（PEL），并与多中心Castleman病（MCD）紧密相关。这些肿瘤发生最多 通常在免疫功能低下的个体中，尤其是患有艾滋病的人。没有具体的疗法 这些恶性肿瘤。 KS是领先的艾滋病恶性肿瘤，在撒哈拉以南非洲是流行病。 KS通常 涉及口腔，可以传播到内脏器官。唾液是KSHV传播的工具。 潜伏期是KSHV和Gammaherpesvirus感染的标志。 KSHV潜在感染的细胞，包括 肿瘤细胞和病毒基因组持续存在为外肿瘤，循环，多拷贝，偶发。坚持下去 增殖细胞，病毒dopipomes必须复制并在有丝分裂之后将其隔离到子细胞核。 肿瘤细胞活力取决于潜在的KSHV感染。 潜伏相关的核抗原（LANA）是在潜伏期中表达的几种病毒基因之一。 拉娜（Lana）介导了KSHV情节维护 缺乏其他病毒基因。除了情节持久性外，拉娜（Lana）在转录中出口重要作用 规定。 表观遗传组蛋白H3赖氨酸4（H3K4）三甲基化（H3K4ME3）标记与主动相关 转录基因，并通过组蛋白甲基转移酶（HMT）复合物沉积。有六个HMT （MLL1-4，set1a/b）在负责通过集合在K4处催化组蛋白H3甲基化的哺乳动物中 领域。 LANA在病毒和宿主染色质处高度富集在H3K4ME3峰 LANA招募到这些站点的功能尚不清楚。 我们发现了与HMT组件的新型Lana相互作用，并且LANA调节了特定 HMT活动。此外，我们发现这种HMT活动对于病毒潜伏期建立至关重要。这项工作将使用 严格，详细的深度方法，以研究这些发现的机械基础。实验会 研究HMT活性在LANA介导的发作持久性中的作用。我们将调查 LANA和HMT染色质靶向病毒和宿主的LANA-HMT相互作用，其对 H3K4ME3沉积和基因表达。实验还将研究拉娜的机制 调节HMT活性及其在病毒潜伏期中的作用。 LANA和HMT活动对于潜伏期至关重要，这 因此，工作为KSHV生物学的基本组成部分提供了新颖而重要的见解。