KSHV Latency Regulation

KSHV 延迟调节

• 批准号: 10520067
• 负责人: Kenneth M Kaye
• 金额: $ 69.2万
• 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/10520067
• 关键词: ASH2L gene; Acquired Immunodeficiency Syndrome; Africa South of the Sahara; Binding; Biochemical; Biology; Cell Nucleus; Cell Proliferation; Cell Survival; Cell division; Cells; ChIP-seq; Childhood Leukemia; Chromatin; Chromatin Remodeling Factor; Chromosomes; Complex; DNA biosynthesis; Daughter; Deposition; Development; Epidemic; Epigenetic Process; Episome; Etiology; Family; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; 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和原发积液的病原体 淋巴瘤(PEL)，与多中心Castleman病(MCD)密切相关。这些肿瘤是最常见的 通常在免疫功能低下的人中，特别是那些患有艾滋病的人。目前还没有特效的治疗方法 这些恶性肿瘤。KS是主要的艾滋病恶性疾病，在撒哈拉以南非洲流行。常见的KS 累及口腔，可扩散至内脏器官。唾液是KSHV的传播媒介。 潜伏期是KSHV和伽马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以染色体外、环状、多拷贝、表型存在。坚持，坚持 在细胞增殖时，病毒上皮体必须复制，并在有丝分裂后分离到子细胞核。 肿瘤细胞的存活依赖于潜伏的KSHV感染。 潜伏期相关核抗原(LANA)是几种以潜伏期表达的病毒基因之一。 LANA介导KSHV Episome的维持，是Episome持续存在的必要条件和充分条件 缺乏其他病毒基因。除了Episome持久性外，LANA还在转录中发挥重要作用 监管。 表观遗传组蛋白H3赖氨酸4(H3K4)三甲基化(H3K4me3)标记与活性相关 转录的基因，并由组蛋白甲基转移酶(HMT)复合体沉积。有六个HMT (MLL1-4，Set1A/B)在哺乳动物中，负责通过SET催化K4处组蛋白H3的甲基化 域。LANA在病毒和宿主染色质的H3K4me3峰上都高度浓缩，但其机制 拉纳招募到这些地点及其在这些地点的职能仍不清楚。 我们已经发现了新的LANA与HMT成分的相互作用，并且LANA调节特定的 HMT活动。此外，我们发现这种HMT活动对于病毒潜伏期的建立至关重要。这项工作将使用 严谨、详细、深入的方法来调查这些发现的机制基础。实验将会 探讨HMT活性在LANA介导的Episome持久性中的作用。我们将调查 LANA-HMT在LANA和HMT靶向病毒和宿主染色质中的相互作用及其对病毒和宿主的影响 H3K4me3沉积与基因表达。实验还将研究LANA的机制 HMT活性的调节及其在病毒潜伏期中的作用。LANA和HMT活动对延迟至关重要，这一点 因此，这项工作为KSHV生物学的一个基本组成部分提供了新的和重要的见解。