The role of host endogenous small RNAs in innate immunity

宿主内源小RNA在先天免疫中的作用

• 批准号: 8499367
• 负责人: Hailing Jin
• 金额: $ 27.04万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499367
• 关键词: Animal Model; Anti-Bacterial Agents; Arabidopsis; Bacteria; Bacterial Drug Resistance; Bacterial Infections; Biogenesis; Biological Models; Biological Process; Code; DNA Methylation; Data; Disease Resistance; Epigenetic Process; Eukaryota; F Box Domain; Functional RNA; Gene Chips; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genome; Host Defense; Immune System Diseases; Immune response; Immune system; Immunity; Infection; Invertebrates; Mammals; Maps; Mediating; MicroRNAs; Molecular; Mouse-ear Cress; Natural Immunity; Organism; Pathway interactions; Plants; Population; Processed Genes; Promoter Regions; Proteins; Pseudomonas syringae; RNA; Regulation; Research; Role; Shotguns; Small Interfering RNA; Small RNA; System; Technology; Tissues; Transcript; Translational Repression; Vesicle; Work; bisulfite; chromatin modification; chromatin remodeling; deep sequencing; defense response; mRNA Expression; mRNA Transcript Degradation; pathogen; public health relevance; response; trafficking

DESCRIPTION (provided by applicant): Organisms, including mammals, invertebrates, and plants have evolved sophisticated and conserved innate immune responses to protect themselves from pathogen attacks. In these systems, host immune responses and disease resistance are achieved by modulation of a large array of genes, but how these processes are regulated is still largely unclear. Small RNAs are non-coding regulatory RNA molecules that control gene expression by mediating mRNA degradation, translational inhibition, or chromatin modification. Our work and those of others have demonstrated a role of host endogenous small RNAs, including microRNAs (miRNAs) and small interfering RNAs (siRNAs), in antibacterial innate immunity. We discovered that several pathogen-induced host endogenous siRNAs, including natural antisense transcripts-derived siRNAs (nat-siRNAs) and long siRNAs (lsiRNAs), facilitate host immune responses by posttranscriptionally silencing the negative regulators of plant immune systems. Epigenetic changes were also observed in bacteria-infected plants, however, the role of small RNA-guided DNA methylation and chromatin modification in plant immunity has not been explored. Using Arabidopsis as a model system and Illumina deep sequencing as a platform, we recently profiled the small RNA population after bacterium-challenge and identified diverse classes of endogenous small RNAs that are regulated by the infection of bacterial pathogens. We hypothesize that these pathogen-responsive small RNAs regulate the expression of genes involved in host immune responses by silencing regulators of host immunity transcriptionally or post-transcriptionally. We propose to investigate the regulation, biogenesis, and function of these pathogen-responsive small RNAs. Specifically, we will perform in depth characterization of several newly identified miRNAs, nat-siRNAs, lsiRNAs, and clustered hc-siRNAs that are particularly regulated by various strains of the bacterium Pseudomonas syringae. Predicted target genes of these small RNAs will be validated and subjected to functional analysis. These targets are likely to be components involved in plant immune response pathways. We will also characterize the hc-siRNAs that directed DNA methylation in response to bacterial infection. We will generate a whole-genome DNA-methylation map before and after bacterial infection, and correlate the siRNAs, DNA methylation, and pathogen-responsive gene expression. The proposed research will significantly advance our understanding of the mechanisms and functions of small RNAs involved in host innate immunity. PUBLIC HEALTH RELEVANCE: Multicellular eukaryotes, including mammals, invertebrates, and plants have evolved sophisticated and conserved innate immune responses to protect themselves from pathogen attack. The proposed research will significantly advance our understanding of the mechanisms and function of small RNA-mediated gene regulation in innate immunity using the model organism Arabidopsis thaliana.

描述（由申请人提供）：生物体，包括哺乳动物、无脊椎动物和植物，已经进化出复杂和保守的先天免疫应答，以保护自身免受病原体攻击。在这些系统中，宿主的免疫反应和抗病性是通过调节大量基因来实现的，但这些过程是如何调节的在很大程度上仍然不清楚。小RNA是通过介导mRNA降解、翻译抑制或染色质修饰来控制基因表达的非编码调节RNA分子。我们的工作和其他人的工作已经证明了宿主内源性小RNA，包括microRNA（miRNA）和小干扰RNA（siRNA）在抗菌先天免疫中的作用。我们发现，几种病原体诱导的宿主内源性siRNA，包括天然反义转录衍生的siRNA（nat-siRNA）和长siRNA（lsiRNA），通过转录后沉默植物免疫系统的负调控因子来促进宿主免疫应答。在细菌感染的植物中也观察到了表观遗传变化，然而，小RNA引导的DNA甲基化和染色质修饰在植物免疫中的作用尚未被探索。 使用拟南芥作为模型系统和Illumina深度测序作为平台，我们最近分析了细菌挑战后的小RNA群体，并鉴定了受细菌病原体感染调控的多种内源性小RNA。我们推测，这些病原体响应性小RNA通过转录或转录后沉默宿主免疫调节因子来调节参与宿主免疫应答的基因的表达。我们建议研究这些病原体响应性小RNA的调控、生物发生和功能。具体而言，我们将深入表征几种新鉴定的miRNAs、nat-siRNA、lsiRNA和簇状hc-siRNA，这些miRNAs特别受细菌假单胞菌的各种菌株的调控。这些小RNA的预测靶基因将被验证并进行功能分析。这些靶标可能是参与植物免疫应答途径的组分。我们还将表征响应细菌感染而指导DNA甲基化的hc-siRNA。我们将在细菌感染前后生成全基因组DNA甲基化图谱，并将siRNA、DNA甲基化和病原体响应基因表达相关联。这项研究将大大促进我们对参与宿主先天免疫的小RNA的机制和功能的理解。 公共卫生关系：包括哺乳动物、无脊椎动物和植物在内的多细胞真核生物已经进化出复杂和保守的先天免疫反应来保护自己免受病原体的攻击。这项研究将大大推进我们对小RNA介导的基因调控机制和功能的理解，在先天免疫中使用模式生物拟南芥。