Alternative pre-mRNA Splicing in Drosophila

果蝇中的选择性前 mRNA 剪接

• 批准号: 8237344
• 负责人: DONALD C RIO
• 金额: $ 45.95万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237344
• 关键词: Address; Affect; Alternative Splicing; Base Pairing; Binding; Binding Sites; Biochemical; Bioinformatics; Biological Assay; Cell Nucleus; Cells; ChIP-seq; Data; Defect; Disease; Drosophila genome; Drosophila genus; Elements; Event; Functional RNA; Funding; Gene Duplication; Gene Expression; Gene Mutation; Genes; Genetic; Genome; Genomics; Grant; Health; Heterogeneous-Nuclear Ribonucleoprotein Group A-B; Homologous Gene; Human; In Vitro; Informatin; Introns; Investigation; Lead; Learning; Link; Malignant Neoplasms; Methods; MicroRNAs; Modeling; Mus; Myotonic Dystrophy; Organism; Pathway interactions; Pattern; Phosphorus; Process; Property; Protein Splicing; Protein Structure Initiative; Proteins; Proteome; Proteomics; RNA; RNA Binding; RNA Interference; RNA Processing; RNA Splicing; RNA-Binding Proteins; RNA-Protein Interaction; Recruitment Activity; Regulation; Regulatory Element; Repression; Repressor Proteins; Research; Role; Site; Small RNA; Split Genes; System; Testing; Testis; Therapeutic Intervention; Tissues; Transcript; Transcriptional Silencer Elements; U1 Small Nuclear Ribonucleoprotein; Work; abstracting; cell type; genome-wide; genome-wide analysis; human disease; in vivo; insight; mRNA Precursor; novel; paralogous gene; protein protein interaction

DESCRIPTION (provided by applicant): PROJECT SUMMARY / ABSTRACT Alternative pre-mRNA splicing in Drosophila. D. Rio - PI Alternative pre-mRNA splicing is an important mechanism for regulating gene expression in metazoans. Indeed, RNA processing is a conduit through which genomic information is transferred to proteomic information. Because most eukaryotic genes are split and have the potential for alternative splicing, a dramatic increase in proteomic diversity among cells, tissues and organisms is a direct consequence of alternative splicing. In fact, it is now recognized that 30-40% of the known human and mouse disease gene mutations affect the splicing process. Thus, understanding how introns are recognized and how patterns of alternative splicing are set up may allow therapeutic intervention. Splicing silencers are a major type of RNA control element generating tissue- or cell type-specific splicing patterns in metazoans. Our previous work has focused on characterization of the tissue-specific Drosophila P element splicing silencer element. Recent work from our group has focused on tissue-specific regulation of alternative splicing and how the action of hnRNP proteins, PSI and the hnRNP A/B family proteins, hrp48, 40, 38 and 36 results in splicing silencer function. We wish to extend these studies to investigate the function of a Drosophila paralog of U2AF, called LS2, that functions as a splicing repressor. Building on previous R21 funding, we will continue investigations of the microRNA pathway protein, Ago-2, in alternative splicing pathways. Finally, using a variety of approaches, we want to identify and functionally characterize new cellular splicing silencers that are controlled by multiple splicing factors. One advantage this proposal has is the small genome size and well-annotated Drosophila genome that allows a comprehensive analysis of both alternative splicing patterns and the genome-wide distribution of RNA binding proteins. Because most eukaryotic genes are split and have the potential for alternative splicing, increased proteomic diversity among cells, tissues and organisms is a direct consequence of alternative splicing. Because the protein factors involved in controlling patterns of alternative splicing have homologs in humans and like humans Drosophila has extensive alternative splicing, results obtained in this system will have direct relevance and application to human health. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Alternative pre-mRNA splicing in Drosophila D Rio - PI Alternative pre-mRNA splicing is a common mechanism for regulating gene expression in metazoans. Because most eukaryotic genes are split and have the potential for alternative splicing, a dramatic increase in proteomic diversity among cells, tissues and organisms is a direct consequence of alternative splicing. In fact, it is now recognized that 30-40% of the known human and mouse disease gene mutations affect the splicing process and because the protein factors involved in controlling patterns of alternative splicing have homologs in humans and like humans Drosophila has extensive alternative splicing, results obtained in this system will have direct relevance and application to human health.

描述（由申请人提供）： 项目摘要/摘要 果蝇中的替代前 mRNA 剪接。 D. Rio - PI 选择性前mRNA剪接是后生动物中调节基因表达的重要机制。事实上，RNA 加工是基因组信息转化为蛋白质组信息的管道。由于大多数真核基因都是分裂的并且具有选择性剪接的潜力，因此细胞、组织和生物体之间蛋白质组多样性的显着增加是选择性剪接的直接结果。事实上，现在人们认识到，30-40% 的已知人类和小鼠疾病基因突变会影响剪接过程。因此，了解内含子是如何被识别的以及选择性剪接的模式是如何建立的可能有助于治疗干预。剪接沉默子是RNA控制元件的主要类型，在后生动物中产生组织或细胞类型特异性剪接模式。我们之前的工作重点是组织特异性果蝇 P 元件剪接消音器元件的表征。我们小组最近的工作重点是选择性剪接的组织特异性调节，以及 hnRNP 蛋白、PSI 和 hnRNP A/B 家族蛋白、hrp48、40、38 和 36 的作用如何导致剪接沉默子功能。我们希望扩展这些研究来研究 U2AF 的果蝇旁系同源物（称为 LS2）的功能，其作为剪接阻遏蛋白。在之前的 R21 资助的基础上，我们将继续研究 microRNA 途径蛋白 Ago-2 的替代剪接途径。最后，我们希望使用多种方法来识别和功能表征由多个剪接因子控制的新型细胞剪接沉默子。该提案的优点之一是果蝇基因组较小且注释良好，可以对选择性剪接模式和 RNA 结合蛋白的全基因组分布进行全面分析。由于大多数真核基因都是分裂的并且具有选择性剪接的潜力，因此细胞、组织和生物体之间蛋白质组多样性的增加是选择性剪接的直接结果。由于参与控制选择性剪接模式的蛋白质因子在人类中具有同源物，并且像人类一样，果蝇也具有广泛的选择性剪接，因此在该系统中获得的结果将与人类健康具有直接相关性和应用。 公共卫生相关性： 项目叙述 果蝇 D Rio 中的选择性前 mRNA 剪接 - PI 选择性前 mRNA 剪接是后生动物中调节基因表达的常见机制。由于大多数真核基因都是分裂的并且具有选择性剪接的潜力，因此细胞、组织和生物体之间蛋白质组多样性的显着增加是选择性剪接的直接结果。事实上，现在人们认识到，30-40%的已知人类和小鼠疾病基因突变会影响剪接过程，并且由于参与控制选择性剪接模式的蛋白质因子在人类中具有同源物，并且像人类一样，果蝇也具有广泛的选择性剪接，因此在该系统中获得的结果将与人类健康具有直接相关性和应用。