Herpesvirus-Chromatin-Programmierung während der De-Novo-Infektion

从头感染期间疱疹病毒染色质编程

• 批准号: 470697882
• 负责人: Professor Dr. Adam Grundhoff
• 金额: --
• 依托单位: Leibniz-Institut für Virologie (LIV)
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/470697882?language=en
• 关键词: Herpesvirus; Chromatin; Programmierung; hrend; der

Nuclear entry of a non-chromatinized, epigenetically naïve DNA molecule is a central event in all herpesvirus infections. Following nuclear delivery, viral episomes can either activate the lytic gene expression cascade, leading to production of viral progeny and host cell death, or acquire latent chromatin states that mediate selective and reversible silencing of lytic genes. Whereas latent chromatin allows the viral genome to persist in a dormant state until a reactivation signal is received, antiviral host defences promote constitutively repressive chromatin states to globally supress invading DNA. If the virus fails to escape or manipulate these defences, viral episomes are permanently silenced or cleared.To date, the chromatin factors and epigenetic pathways governing successful establishment of latent chromatin are only partially understood. Given their evolutionary relationship, we hypothesise that as of yet undiscovered and fundamental principles are shared among different herpesviruses. To address this hypothesis, we here will perform a comparative analysis of two human herpesviruses: The gammaherpesvirus Kaposi sarcoma-associated herpesvirus (KSHV) and the alphaherpesviruses varicella zoster virus (VZV). Based on our previous observations, we hypothesize that both viruses exploit default host pathways that have evolved to rapidly recruit polycomb repressive complexes (PRC) to CpG-rich DNA molecules devoid of DNA methylation. Instead of constitutive heterochromatinization that may be imposed by components of PML nuclear bodies (PML-NBs), PRC recruitment then allows viral episomes to acquire facultative heterochromatin states to establish and maintain latency. While we therefore postulate PRC-mediated suppression to be a common denominator of latency, we also expect that initial assembly as well as maturation of viral chromatin proceed in a spatially and/or temporally distinct fashion for each virus. We will employ relevant in vitro latency models, transcriptome/epigenome analyses and live cell imaging to perform a spatiotemporal investigation of the latency establishment phase to decipher the mechanisms that govern viral chromatin programming, and to identify the key viral and cellular factors involved in this process. In a putative second funding period, we plan to extend our findings to other viruses with the explicit goal of developing a unified model of early chromatin regulation in DNA virus infection.

非染色质化的表观遗传naïve DNA分子的核进入是所有疱疹病毒感染的中心事件。在核传递后，病毒发作可以激活裂解基因级联表达，导致病毒子代的产生和宿主细胞死亡，或者获得潜伏的染色质状态，介导裂解基因的选择性和可逆沉默。潜伏染色质允许病毒基因组持续处于休眠状态，直到接收到再激活信号，而抗病毒宿主防御促进组成性抑制染色质状态，以全局抑制入侵的DNA。如果病毒未能逃脱或操纵这些防御，病毒发作将被永久沉默或清除。迄今为止，染色质因子和控制成功建立潜在染色质的表观遗传途径仅被部分理解。鉴于它们的进化关系，我们假设尚未发现的基本原理在不同的疱疹病毒之间是共享的。为了解决这一假设，我们将对两种人类疱疹病毒进行比较分析：伽玛疱疹病毒卡波西肉瘤相关疱疹病毒（KSHV）和甲型疱疹病毒水痘带状疱疹病毒（VZV）。基于我们之前的观察，我们假设这两种病毒都利用了默认的宿主途径，这些途径已经进化到快速招募多梳抑制复合物（PRC）到缺乏DNA甲基化的富含cpg的DNA分子。与其由PML核小体（PML- nb）组成的本构异染色质化不同，PRC的招募允许病毒发作获得同时性异染色质状态，以建立和维持潜伏期。因此，虽然我们假设prc介导的抑制是潜伏期的共同分母，但我们也期望每种病毒的初始组装和病毒染色质的成熟以空间和/或时间上不同的方式进行。我们将采用相关的体外潜伏期模型、转录组/表观基因组分析和活细胞成像来对潜伏期建立阶段进行时空研究，以破译控制病毒染色质编程的机制，并确定参与这一过程的关键病毒和细胞因素。在假定的第二个资助期，我们计划将我们的发现扩展到其他病毒，明确的目标是开发DNA病毒感染中早期染色质调控的统一模型。