Functional Characterization of Herpesvirus-Activated Noncoding Retrotransposon RNAs

疱疹病毒激活的非编码反转录转座子 RNA 的功能表征

• 批准号: 9975697
• 负责人: Britt A Glaunsinger
• 金额: $ 18.9万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-10 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975697
• 关键词: Address; Antiviral Agents; Antiviral Response; Blindness; Cell Nucleus; Cells; Cellular Stress; Chickenpox; Chromatin; Code; Complex; Cytoplasm; DNA Polymerase III; DNA Virus Infections; DNA Viruses; Data; Disease; Double-Stranded RNA; Elements; Epigenetic Process; Eukaryotic Cell; Exposure to; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genome; Herpes zoster disease; Herpesviridae; Herpesviridae Infections; Herpesvirus Type 3; Homeostasis; Host Defense; Human; Human Herpesvirus 8; Immune system; Immunization; In Vitro; Individual; Infection; Inflammatory Response; Innate Immune Response; Interferons; Link; Malignant Neoplasms; Maps; Mediating; Messenger RNA; Missense Mutation; Modality; Mus; Natural Immunity; Nuclear; Outcome; Pathology; Pathway interactions; Pattern; Plasmids; Play; Polymerase; Production; Proteins; RNA; RNA Polymerase III; Regulator Genes; Repetitive Sequence; Research; Retrotransposon; Role; Shapes; Signal Pathway; Signal Transduction; Somatic Cell; Technology; Testing; Tissues; Transcript; Transcriptional Regulation; Untranslated RNA; Viral; Viral Pathogenesis; Virus Diseases; Virus Replication; antiviral immunity; cell type; cytokine; experimental study; gammaherpesvirus; immune activation; innate immune pathways; insight; pathogen; pathogenic virus; response; sensor; tripolyphosphate

The advancement of sequencing technologies has resulted in the discovery of numerous types of non-coding RNAs (ncRNA) that play important role in both tissue homeostasis and disease pathology. Additionally, several studies have identified host and pathogen-encoded ncRNA whose expression patterns are associated with viral pathogenesis, host defense and activation from latency. One specific class of ncRNA that has been shown to modulate viral replication and inflammatory responses in mouse and human cells, respectively, are the short interspersed nuclear elements (SINEs), termed B1-B4 in mice and Alu in humans. These repetitive elements are epigenetically silenced in healthy somatic cells but can be induced and transcribed by RNA polymerase III (Pol3) upon exposure to various cellular stresses , including infection with a variety of DNA viruses. Recent studies suggest that SINE ncRNA expression can influence viral and host gene expression and NFκB signaling during infection with the murine gammaherpesvirus MHV68, a close relative of Kaposi's sarcoma-associated herpesvirus. Additional studies have linked SINE expression to increased transcription of interferon-stimulated genes (ISG) . Given that SINE ncRNAs accumulate in the nucleus and the cytoplasm, how their gene regulatory and signaling activities are coordinated in each compartment is a fundamental question in the field. We will address this by first constructing a SINE locus activation map in cells infected with alpha or gammaherpesviruses, which will be used to identify direct SINE ncRNA-driven gene expression signatures in the nucleus and their consequences for viral replication. We will then identify which components of the innate immune pathway in the cytoplasm are involved in sensing natively transcribed SINE ncRNAs. Collectively, these results will provide new mechanistic insights into how these “self” ncRNAs function to influence the gene expression landscape during DNA virus infection.

测序技术的进步已经导致发现了许多类型的非编码基因。 RNA（ncRNA）在组织稳态和疾病病理学中起重要作用。此外，若干 研究已经鉴定了宿主和病原体编码的ncRNA，其表达模式与 病毒的发病机制、宿主防御和潜伏激活。一类特殊的ncRNA， 显示分别在小鼠和人细胞中调节病毒复制和炎症反应， 短散在核元件（西内斯），在小鼠中称为B1-B4，在人类中称为Alu。这些重复 在健康的体细胞中，表观遗传沉默元件，但可以被RNA诱导和转录 聚合酶III（Pol 3）在暴露于各种细胞应激时 包括感染多种DNA 病毒最近的研究表明，SINE ncRNA的表达可以影响病毒和宿主基因的表达 小鼠γ疱疹病毒MHV 68（Kaposi的近亲）感染期间NFκB信号传导 肉瘤相关疱疹病毒另外的研究已经将SINE表达与转录的增加联系起来， 干扰素刺激基因（ISG）。鉴于SINE ncRNA在细胞核中积累， 细胞质中，它们的基因调控和信号传导活动如何在每个隔室中协调， 这个领域的基本问题。我们将通过首先构建一个SINE位点激活图来解决这个问题。 感染α或γ疱疹病毒的细胞，其将用于鉴定直接SINE ncRNA驱动的基因 细胞核中的表达特征及其对病毒复制的影响。然后我们将确定 细胞质中先天免疫途径的组分参与感知天然转录的SINE ncRNA。总的来说，这些结果将为这些“自我”ncRNA的功能提供新的机制见解 影响DNA病毒感染期间的基因表达景观。