Regulation of Viral Chromatin Architecture During EBV Latency

EBV 潜伏期病毒染色质结构的调节

基本信息

批准号：
10219524
负责人：
Italo Tempera
金额：
$ 45.76万
依托单位：
WISTAR INSTITUTE
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：
2018-04-25 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219524
关键词：
3-Dimensional ADP ribosylation Adenosine Diphosphate Ribose Adopted Affect Anabolism Anchorage-Independent Growth Architecture B-Lymphocytes Biochemical Biological Assay Biological Models Cell Proliferation Cell physiology Cells ChIP-seq Charge Chromatin Chromatin Loop Chromatin Structure Chromosomes Combined Modality Therapy Complex Data Development Drug Targeting EBV-associated disease EZH2 gene Epigenetic Process Episome Epstein-Barr Virus Infections Epstein-Barr Virus latency Epstein-Barr Virus-Related Malignant Neoplasm FDA approved Family Gene Expression Gene Expression Profile Gene Silencing Genes Genetic Transcription Genome Goals HIV Heterogeneity Histones Human Human Herpesvirus 4 Immune response Immune system Immunocompetent Immunocompromised Host Immunologic Surveillance In Vitro Individual Infectious Mononucleosis LMP1 Latent virus infection phase Link Lymphoma Maintenance Malignant Neoplasms Maps Mediating Memory B-Lymphocyte Metabolism Methods Methylation Modification Molecular Conformation Pathogenicity Pathology Pattern Pharmaceutical Preparations Pharmacology Play Poly(ADP-ribose) Polymerases Polycomb Polymers Population Post-Translational Protein Processing Proliferating Proteins Reaction Regulation Role Stomach Carcinoma Structure Switch Genes Testing Therapeutic Time Transplant Recipients Viral Viral Genes Viral Genome Viral Proteins Virus Virus Latency Virus Replication Work base cell type chromatin modification chromosome conformation capture epigenetic regulation epigenetic therapy gammaherpesvirus genome sequencing genome-wide inhibitor/antagonist latent infection member multicatalytic endopeptidase complex mutant novel novel strategies novel therapeutic intervention pathogen prevent programs promoter therapeutic target three dimensional structure virus genetics

项目摘要

Epstein-Barr virus (EBV) is a human gamma herpesvirus 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 infectious mononucleosis, different types of lymphomas and gastric carcinoma. This heterogeneity in EBV-associated diseases may reflect the different gene expression programs that EBV adopts in different cell types and host-cell conditions. Epigenetic modifications and alternative viral chromatin conformations contribute to the establishment and maintenance of these alternative viral gene expression programs, which are referred to as latency types. Although we know that chromatin- organizing factors, such as CTCF, affect the epigenetic state of the EBV episome we know little about the mechanisms that govern EBV genome plasticity and function and how EBV manipulates the host epigenetic machinery to avoid complete epigenetic silencing of viral latent promoters. The long-term goal of this project is to understand how EBV hijacks host epigenetic machinery to establish a latent infection, regulating both viral and host gene expression. Post-translational modifications regulate several cellular processes including the host response against pathogens. Poly-ADP-ribosylation consists of the attachment of negatively charged polymers of ADP-ribose to acceptor proteins. The reaction is catalyzed by members of the Poly(ADP-ribose) polymerase (PARP) family. In previous work, we demonstrated that PARP1 regulates EBV replication by interacting with the viral genome. Our preliminary work provides new genome wide and biochemical data that reveals for the first time that LMP1 activates PARP1 and that PARP1 activity prevents EZH2 from silencing the viral genome. Thus, we hypothesize that the EBV protein LMP1 affects viral gene expression by altering chromatin structure through PARP1/EZH2 interaction. Our project aims to fill the gap in our understanding of the epigenetic regulation of the EBV genome. To achieve our goal, we aim to: 1) how PARP1 activation regulates EBV latency programs; and 2) determine if EZH2 plays a role in regulating EBV latency. Completion of this project will reveal new mechanisms by which EBV can contribute to maintain and switch between different gene expression programs observed in infected cells. It will also identify new potential therapeutic targets for EBV infection and EBV-associated malignancies.

Epstein-Barr 病毒 (EBV) 是一种人类 γ 疱疹病毒，可感染大约 95% 的人群，并作为染色质相关多拷贝附加体潜伏在记忆 B 细胞中。 EBV 感染与多种病理有因果关系，包括传染性单核细胞增多症、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 EBV 在不同细胞类型和宿主细胞条件下采用的不同基因表达程序。表观遗传修饰和替代病毒染色质构象有助于这些替代病毒基因表达程序的建立和维持，这些程序被称为潜伏类型。尽管我们知道染色质组织因子（例如 CTCF）会影响 EBV 附加体的表观遗传状态，但我们对控制 EBV 基因组可塑性和功能的机制以及 EBV 如何操纵宿主表观遗传机制以避免病毒潜伏的完全表观遗传沉默知之甚少。发起人。该项目的长期目标是了解 EBV 如何劫持宿主表观遗传机制以建立潜伏感染，从而调节病毒和宿主基因表达。翻译后修饰调节多种细胞过程，包括宿主针对病原体的反应。聚-ADP-核糖基化由带负电荷的 ADP-核糖聚合物与受体蛋白的连接组成。该反应由聚（ADP-核糖）聚合酶（PARP）家族成员催化。在之前的工作中，我们证明了 PARP1 通过与病毒基因组相互作用来调节 EBV 复制。我们的初步工作提供了新的全基因组和生化数据，首次揭示了 LMP1 激活 PARP1，并且 PARP1 活性阻止 EZH2 沉默病毒基因组。因此，我们假设 EBV 蛋白 LMP1 通过 PARP1/EZH2 相互作用改变染色质结构来影响病毒基因表达。我们的项目旨在填补我们对 EBV 基因组表观遗传调控的理解空白。为了实现我们的目标，我们的目标是：1）PARP1激活如何调节EBV潜伏期程序； 2) 确定 EZH2 是否在调节 EBV 潜伏期中发挥作用。该项目的完成将揭示 EBV 有助于维持和在受感染细胞中观察到的不同基因表达程序之间切换的新机制。它还将确定 EBV 感染和 EBV 相关恶性肿瘤的新潜在治疗靶点。