Role of Nuclear Lamina in the epigenetic regulation of Epstein-Barr Virus Infection

核层在 Epstein-Barr 病毒感染的表观遗传调控中的作用

基本信息

批准号：
9293955
负责人：
Italo Tempera
金额：
$ 19.5万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-10 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9293955
关键词：
Adopted Affect African Burkitt&apos s lymphoma Antiviral Agents Architecture B Cell Proliferation B-Lymphocytes Binding Biological Biological Assay Cell Line Cell Nucleus Cell Proliferation Cells ChIP-seq Chromatin Chromosome Mapping Chromosomes Coupled DNA DNA Viruses Data Detection EBV-associated disease Epigenetic Process Episome Epstein-Barr Virus Infections Epstein-Barr Virus latency Epstein-Barr Virus-Related Malignant Neoplasm Gene Expression Genes Genetic Transcription Genomic Segment Genomic approach Heterogeneity Histones Human Human Herpesvirus 4 Immune Immune system Individual Infection Lamin B1 Lamins Latent Virus Life Lymphoma Lymphoproliferative Disorders Maintenance Malignant Neoplasms Maps Mediating Memory B-Lymphocyte Modeling Modification Molecular Molecular Conformation Non-Hodgkin&apos s Lymphoma Nuclear Nuclear Inner Membrane Nuclear Lamina Pathogenesis Pathology Play Population Proteins Regulation Reporting Repression Role Stomach Carcinoma Time Translational Research Type III Epithelial Receptor Cell Viral Viral Gene Expression Regulation Viral Genes Viral Genome Virus Virus Diseases Virus Latency Work base biological research cell type cellular targeting epigenetic regulation epigenome genome-wide histone modification innovation insight latent gene expression mutant novel novel therapeutic intervention pathogen programs promoter transcriptome sequencing viral DNA virology whole genome

项目摘要

Project Summary Epstein-Barr virus (EBV) is a human gammaherpes virus that infects approximately 95% of the population and remains latent in memory B cells as a chromatin-associated multicopy episome. EBV infection is causally associated with several pathologies including different types of lymphomas and gastric carcinoma. This heterogeneity in EBV-associated diseases may reflect the different gene expression programs that the virus adopts in different cell types and host-cell conditions. We and others have shown that epigenetic modifications contribute to establish and maintain these alternative viral gene expression programs during latency. We identified that cellular factors such as CTCF affect the EBV epigenome; however, we still lack a complete understanding of mechanisms regulating EBV latency. Interactions with different nuclear sub-compartments, including the nuclear lamina, contribute to regulating the expression of underlying DNA regions. The nuclear lamina is a protein meshwork that underlies the inner nuclear membrane. In addition to providing structural support for the nucleus, the nuclear lamina is crucial for the proper organization of chromatin at the nuclear periphery. As such, genes that are localized to the nuclear periphery are frequently poorly expressed. Since CTCF is known to associate with the nuclear lamina, this supports the idea that the nuclear lamina contributes to the regulation of EBV gene expression. However, the role of the nuclear lamina as key regulator of the EBV epigenome has yet to be explored. We report here, for the first time, a potential interaction between the nuclear lamina and the EBV chromosome, which may regulate viral chromatin. At the present it remains unknown if EBV localizes at the nuclear periphery and how this association can affect viral genome functions. Our project aims to fill this gap by exploring the role of nuclear lamina-EBV interaction on the epigenetic regulation of the EBV genome. We hypothesize that the nuclear lamina contributes to the epigenetic control of EBV gene expression during latency, and that CTCF plays a role in the EBV-nuclear lamina interaction. Here we will use a genomic approach in EBV mutants and different EBV positive B-cell lines to: 1) identify which EBV genomic regions are associated with the nuclear lamina; the chromatin state of these lamin-associated regions; and the role of CTCF in mediating the interaction between lamins and the EBV genome; and 2) determine the role of nuclear lamina association on EBV gene expression and EBV chromatin organization. Our studies will provide new insight into the mechanism regulating EBV latent gene expression. Considering the role of nuclear lamina in the infection cycles of other viruses our proposal can have significant biological and translational implications for the broader virology field.

项目概要 EB 病毒 (EBV) 是一种人类伽马疱疹病毒，可感染约 95% 的人类群体并作为染色质相关的多拷贝附加体潜伏在记忆 B 细胞中。 EB病毒感染与多种病理学有因果关系，包括不同类型的淋巴瘤和胃癌。 EBV 相关疾病的这种异质性可能反映了不同基因表达程序病毒适应不同的细胞类型和宿主细胞条件。我们和其他人已经证明表观遗传修饰有助于建立和维持这些替代病毒基因表达程序延迟。我们发现 CTCF 等细胞因素会影响 EBV 表观基因组；然而，我们仍然缺乏一个完全了解调节 EBV 潜伏期的机制。与不同核子区室（包括核层）的相互作用有助于调节底层 DNA 区域的表达。核层是一个蛋白质网络内核膜。除了为细胞核提供结构支持外，核纤层还具有对于核外围染色质的正确组织至关重要。因此，定位于核外围经常表达不佳。由于 CTCF 已知与核有关核纤层，这支持了核纤层有助于调节 EBV 基因表达的观点。然而，核纤层作为 EBV 表观基因组关键调节因子的作用仍有待探索。我们在这里首次报告核纤层和 EBV 之间潜在的相互作用染色体，可能调节病毒染色质。目前尚不清楚 EBV 是否定位于核外围以及这种关联如何影响病毒基因组功能。我们的项目旨在填补这一空白通过探索核纤层-EBV 相互作用对 EBV 基因组表观遗传调控的作用。我们假设核纤层有助于 EBV 基因表达的表观遗传控制潜伏期，并且 CTCF 在 EBV-核层相互作用中发挥作用。在这里我们将使用基因组 EBV 突变体和不同 EBV 阳性 B 细胞系的方法：1) 鉴定哪些 EBV 基因组区域与核层相关；这些核纤层蛋白相关区域的染色质状态；和角色 CTCF 介导核纤层蛋白和 EBV 基因组之间的相互作用； 2）确定核的作用 EBV 基因表达和 EBV 染色质组织的层关联。我们的研究将提供新的深入了解调节 EBV 潜伏基因表达的机制。考虑到核纤层的作用其他病毒的感染周期我们的建议可能具有重大的生物学和转化意义为更广泛的病毒学领域。