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Genomics of RNA Editing: Identification and Regulation

RNA 编辑的基因组学：识别和调控

基本信息

批准号：
8506659
负责人：
Jin Billy Li
金额：
$ 31.4万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-06 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8506659
关键词：
ADAR1 Adenosine Adult Amyotrophic Lateral Sclerosis Architecture Atlases Base Sequence Biological Biological Assay Biological Process Cataloging Catalogs Cells Chemicals Code Cognition Collection Communities Computational Technique Computer Analysis DNA DNA Sequence DRADA2b protein Data Data Set Depression and Suicide Development Disease Embryo Enzymes Epilepsy Evolution Foundations Frequencies Functional RNA Future Gene Expression Profile Gene Expression Regulation Generations Genes Genetic Genome Genomics Glioma Goals Homeostasis Human Human Development Human Genome Project Indium Individual Inosine Investigation Knowledge Lead Light Macaca mulatta Maintenance Malignant Neoplasms Mammalian Cell Mammals Maps Measures Methods Modification Molecular Monkeys Mouse Strains Mus Mutate Nervous system structure Neurobiology Neurologic Organism Pan Genus Pathogenesis Phenotype Plant Roots Primates Process RNA RNA Editing RNA Sequences Reading Regulation Research Resources Role Signal Transduction Site Specificity Staging Techniques Technology Therapeutic Intervention Time Tissues Work adenosine deaminase base comparative comparative genomics computer framework computerized tools empowered exome sequencing expectation genome sequencing human disease human tissue innovation insight malignant neurologic neoplasms mammalian genome nervous system disorder public health relevance relating to nervous system spatiotemporal success tool transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Through the efforts of the Human Genome Project and other large-scale investigations, it has become clear that the molecular origins of human complexity, disease, and distinctness from other organisms are rooted in more than just the number of genes in the genome. RNA editing, the post-transcriptional alteration of genome-encoded information by chemical modification of individual RNA bases, provides a potentially powerful way to diversify the set of RNAs expressed in an organism's tissues over time. Aberrant RNA editing has been implicated in human neurological diseases such as amyotrophic lateral sclerosis, epilepsy, depression, suicide, glioma, and cancers, and may have contributed to the evolutionary development of human neurobiology and cognition. While numerous RNA editing sites have been identified to date, we are still far from possessing a complete list of RNA editing targets particularly in the coding regions, thus hindering a full understanding of the complexity of this process and its potential for therapeutic intervention. We propose to extend our recent success at developing experimental and computational frameworks to the generation of a comprehensive atlas of RNA editing sites in humans and mice. By combining multiple validated techniques, we will rigorously quantitate RNA editing in a spectrum of matched human and mouse tissues from multiple developmental stages. We will use this approach to extend our analysis to RNA editing in other primates such as chimpanzees and rhesus macaque monkeys, with the expectation of uncovering the contributions of RNA editing to conserved functions as well as to human-specific neural evolution. We will also carry out large-scale computational analysis to search for RNA editing-related functional elements in the annotated genomic and transcriptomic datasets. Finally, we propose to use a variety of mouse strains mutated for the enzymes that perform RNA editing to elucidate the regulation of RNA editing. Taken together, the goals of this proposed project will deepen our understanding of the molecular basis of RNA editing, generate a set of experimental and computational tools to drive innovation in the RNA editing field, and unravel the network of signals that regulate RNA editing spatiotemporally, thus bringing us closer to the goal of manipulating RNA editing to alleviate human disease.

描述（由申请人提供）：通过人类基因组计划和其他大规模研究的努力，已经清楚的是，人类复杂性、疾病以及与其他生物体的独特性的分子起源不仅仅植根于基因组中的基因数量。 RNA 编辑是通过对单个 RNA 碱基进行化学修饰来对基因组编码信息进行转录后改变，它提供了一种潜在的强大方法，可以随着时间的推移使生物体组织中表达的 RNA 集多样化。异常的RNA编辑与人类神经系统疾病有关，如肌萎缩侧索硬化症、癫痫、抑郁症、自杀、神经胶质瘤和癌症，并可能促进了人类神经生物学和认知的进化发展。虽然迄今为止已经鉴定出许多 RNA 编辑位点，但我们还远未拥有完整的 RNA 列表编辑目标，特别是编码区域的目标，从而阻碍了对该过程的复杂性及其治疗干预潜力的充分理解。我们建议将我们最近在开发实验和计算框架方面取得的成功扩展到人类和小鼠 RNA 编辑位点的综合图谱的生成。通过结合多种经过验证的技术，我们将严格定量来自多个发育阶段的一系列匹配的人类和小鼠组织中的 RNA 编辑。我们将使用这种方法将我们的分析扩展到其他灵长类动物（例如黑猩猩和恒河猴）的 RNA 编辑，期望揭示 RNA 编辑对保守功能以及人类特定神经进化的贡献。我们还将进行大规模计算分析，以在注释的基因组和转录组数据集中寻找与RNA编辑相关的功能元件。最后，我们建议使用多种进行 RNA 编辑的酶突变的小鼠品系来阐明 RNA 编辑的调控。总而言之，该项目的目标将加深我们对RNA编辑分子基础的理解，生成一套实验和计算工具来推动RNA编辑领域的创新，并解开调节RNA编辑时空的信号网络，从而使我们更接近操纵RNA编辑以减轻人类疾病的目标。