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Epigenetic Regulation During the HPV Life Cycle

HPV 生命周期中的表观遗传调控

基本信息

批准号：
10520010
负责人：
CARY A MOODY
金额：
$ 34.86万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-06 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10520010
关键词：
Affect Alternative Splicing Back Binding Biotin Cancer Etiology Cell Cycle Cell Cycle Deregulation Cell Cycle Regulation Cell Differentiation process Cell physiology Cells Chromatin Chromatin Structure Chromosomes Clinical Treatment Coupled DNA DNA Repair Data Deposition Development Disease Dominant-Negative Mutation Epigenetic Process Episome Epithelium Etiology Exhibits Gene Expression Genetic Transcription Genital Genitalia Genome Genome Stability Genomic Instability Goals HPV-High Risk Half-Life Head and Neck Cancer Histone Code Histone H3 Histones Human Human Papilloma Virus Vaccine Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human papilloma virus 31 Infection Knowledge Life Cycle Stages Ligase Link Location Lysine Maintenance Malignant Neoplasms Malignant neoplasm of cervix uteri Mass Spectrum Analysis Mediating Methyltransferase Modification Pathogenesis Pathway interactions Phase Post-Translational Protein Processing Process Production Productivity Proteins RNA Processing RNA Splicing Reader Risk Factors Role Site Stratified Epithelium Testing Transcription Elongation Tumor Suppressor Proteins Undifferentiated Viral Viral Genome Viral Pathogenesis Viral Physiology Virion Virus Replication Work cancer type driving force epigenetic regulation high risk histone modification insight knock-down multicatalytic endopeptidase complex new therapeutic target novel overexpression recruit therapeutic development therapeutic target viral DNA viral RNA

项目摘要

The productive phase of the HPV life cycle is restricted to the uppermost layer of the epithelium, in cells that have normally exited the cell cycle. The E7 protein alters cell cycle regulation to push differentiating cells back into the cell cycle, allowing for productive replication and virion production. Cell cycle deregulation by E7 leads to genomic instability that is a driving force in cancer development. Our long-term goal is to understand mechanisms that regulate productive viral replication, which is important to understanding how HPV causes cancer. HPV genomes are histone-associated, though the impact of histone post-translational modifications on the viral life cycle is unclear. This proposal focuses on understanding how HPV utilizes the SETD2 methyltransferase to facilitate viral replication. SETD2 adds the trimethyl mark to histone H3 on lysine 36 (H3K36me3) during transcription elongation and regulates multiple cellular processes through the recruitment of numerous effector proteins to H3K36me3. We will identify the mechanisms by which SETD2 activity contributes to viral replication and determine how E7 increases the stability of SETD2. We hypothesize that HPV epigenetically regulates the viral life cycle through SETD2-mediated H3K36me3 on viral, as well as cellular chromatin. Specific Aims to test this are: (1) To determine the mechanism by which SETD2 facilitates viral replication by examining whether SETD2 knockdown affects transcription, RNA processing and DNA repair on viral genomes, as well as by identifying H3K36me3 readers bound to HPV DNA. (2) To determine the mechanism by which E7 increases the protein stability of SETD2 by examining known modulators of SETD2 stability, as well as by identifying SETD2 interacting partners though a non-biased approach using a BirA- tagged SETD2 coupled with mass spectrometry. Since SETD2 is essential to the maintenance of genomic stability, it is important to understand how HPV utilizes this epigenetic modifier to facilitate viral replication. Understanding how SETD2 activity promotes the viral life cycle will provide insight into mechanisms of viral persistence, as well as genomic instability. These studies may also identify therapeutic targets for the treatment of HPV-associated diseases.

HPV生命周期的生产阶段仅限于上皮的最上层，在正常退出细胞周期的细胞中。E7蛋白改变细胞周期调节，将分化细胞推回到细胞周期，允许生产性复制和病毒体生产。E7导致的细胞周期失调导致基因组不稳定，这是癌症发展的驱动力。我们的长期目标是了解调节生产性病毒复制的机制，这对于了解HPV如何导致癌症非常重要。HPV基因组与组蛋白相关，尽管组蛋白翻译后修饰对病毒生命周期的影响尚不清楚。该提案的重点是了解HPV如何利用SETD 2甲基转移酶促进病毒复制。SETD2在转录延伸期间将三甲基标记添加到赖氨酸36（H3K36me3）上的组蛋白H3，并通过将许多效应蛋白募集到H3K36me3来调节多个细胞过程。我们将确定SETD 2活性有助于病毒复制的机制，并确定E7如何增加SETD 2的稳定性。我们假设HPV通过在病毒和细胞染色质上的SETD2介导的H3K36me3表观遗传学调节病毒的生命周期。具体目的是：（1）通过检查SETD2敲低是否影响病毒基因组上的转录、RNA加工和DNA修复，以及通过鉴定与HPV DNA结合的H3K36me3阅读器，确定SETD2促进病毒复制的机制。(2)通过检查已知的SETD2稳定性调节剂，以及通过使用BirA标记的SETD2与质谱联用的非偏倚方法鉴定SETD2相互作用配偶体，确定E7增加SETD2蛋白稳定性的机制。由于SETD2对维持基因组稳定性至关重要，因此了解HPV如何利用这种表观遗传修饰剂促进病毒复制非常重要。了解SETD 2活性如何促进病毒的生命周期将有助于深入了解病毒持久性以及基因组不稳定性的机制。这些研究还可以确定治疗HPV相关疾病的治疗靶点。