EPIGENETIC REGULATION OF THE INITIATION OF AN SV40 LYTIC INFECTION

SV40 裂解性感染启动的表观遗传调控

• 批准号: 8231064
• 负责人: Barry Ira Milavetz
• 金额: $ 41.4万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-07 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231064
• 关键词: Binding; Biological; Cell physiology; Cells; Chromatin; DNA Tumor Viruses; DNA Virus Infections; DNA Viruses; Defense Mechanisms; Epigenetic Process; Event; Genetic Transcription; Histones; Infection; Investigation; Lead; Life Cycle Stages; Lytic Phase; Methylation; Modeling; Modification; Molecular Biology; Pattern; Play; Procedures; Process; Publishing; Regulation; Research; Role; Simian virus 40; Staging; Testing; Therapeutic Intervention; Time; Transcriptional Activation; Viral; Virion; Virus; Virus Diseases; Work; design; histone methyltransferase; histone modification; human disease; innovation; metaplastic cell transformation; novel; response; therapy design

DESCRIPTION (provided by applicant): Using SV40 as a model for infection by DNA viruses, the proposed studies will contribute to our understanding of the role that epigenetics plays in determining the fate of viral chromatin during the initiation of an infection. Our central hypothesis is that DNA viruses organized into chromatin contain histone modifications that activate competing cellular processes during the early stages of infection which result in either activation of viral transcription or inactivation of the incoming chromatin. The specific aims are: (1) To characterize the SV40 epigenomes present in virions and minichromosomes during the initiation of infection, (2) To correlate changes in the epigenomes of minichromosomes with the initiation of early transcription, and (3) To characterize the role of epigenetic modifications present in viral chromatin in the establishment of a subsequent infection. The histone modifications present in the epigenomes of SV40 chromatin from virions and minichromosomes isolated early in infection or undergoing activation of transcription will be determined using various ChIP procedures. The SV40 epigenomes will be defined by the presence of distinct combinations of histone modifications and correlated with the activation of early transcription. The role of epigenetic modifications in determining the fate of an infecting SV40 minichromosome will be analyzed by inhibiting histone methylation with siRNAs targeting the relevant histone methylases and characterizing the effects of inhibition on virion formation and establishment of an infection. The proposed work is innovative, because for the first time the role of epigenetic regulation in defining the histone modifications present in viral chromatin and the subsequent fate of the infecting viral chromatin will be determined. The proposed work is significant for two reasons. First, understanding the role of epigenetics in determining the fate of chromatin infecting a cell may lead to therapeutic interventions designed to reduce or eliminate an infection. Second, confirmation of our central hypothesis would lead to a significant advance in our understanding of the role of epigenetics in regulating the competing viral and cellular processes necessary for the establishment of an infection. PUBLIC HEALTH RELEVANCE: The proposed studies will be the first characterization of the role of epigenetics in the establishment of a viral infection. The results obtained will significantly add to our knowledge of the role of histone modifications in the initiation of early transcription and the activation of cellular processes designed to limit infection. SV40 has been an excellent model to study basic eukaryotic molecular biology and the mechanisms underlying cellular transformation by DNA tumor viruses. The proposed research will extend this use as a model to the investigation of the role of epigenetic regulation in establishing a viral infection. The results obtained will be relevant to other viral human diseases and to a basic understanding of the mechanisms and functions of epigenetic regulation.

描述（由申请方提供）：使用SV40作为DNA病毒感染的模型，拟定的研究将有助于我们理解表观遗传学在感染开始期间决定病毒染色质命运方面的作用。我们的中心假设是，组织成染色质的DNA病毒含有组蛋白修饰，其在感染的早期阶段激活竞争性细胞过程，这导致病毒转录的激活或进入的染色质的失活。具体目标是：（1）表征感染开始期间病毒粒子和微型染色体中存在的SV 40表观基因组，（2）将微型染色体表观基因组的变化与早期转录的开始相关联，以及（3）表征病毒染色质中存在的表观遗传修饰在建立后续感染中的作用。将使用各种ChIP程序确定来自感染早期分离或经历转录激活的病毒体和微型染色体的SV 40染色质的表观基因组中存在的组蛋白修饰。SV40表观基因组将通过组蛋白修饰的不同组合的存在来定义，并与早期转录的激活相关。将通过用靶向相关组蛋白甲基化酶的siRNA抑制组蛋白甲基化并表征抑制对病毒体形成和感染建立的影响来分析表观遗传修饰在确定感染性SV 40微型染色体命运中的作用。拟议的工作是创新的，因为第一次定义组蛋白修饰存在于病毒染色质中的表观遗传调控的作用和随后的感染病毒染色质的命运将被确定。拟议的工作具有重要意义，原因有二。首先，了解表观遗传学在决定感染细胞的染色质命运中的作用可能会导致旨在减少或消除感染的治疗干预。第二，我们的中心假设的证实将导致我们在理解表观遗传学在调节建立感染所必需的竞争性病毒和细胞过程中的作用方面取得重大进展。 公共卫生相关性：拟议的研究将是表观遗传学在建立病毒感染中的作用的第一个表征。所获得的结果将显着增加我们的知识组蛋白修饰的作用，在启动早期转录和激活的细胞过程，旨在限制感染。SV40是研究真核生物基础分子生物学和DNA肿瘤病毒转化细胞机制的理想模型。拟议的研究将扩大这种使用作为一个模型，以调查表观遗传调节在建立病毒感染的作用。所获得的结果将与其他病毒性人类疾病有关，并对表观遗传调控的机制和功能有基本的了解。