Genomics of RNA Editing: Identification and Regulation

描述(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，人们已经清楚地认识到，人类复杂性、疾病和与其他生物的区别的分子起源不仅仅是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的改变，为随着时间的推移使生物体组织中表达的一组RNA多样化提供了一种潜在的强有力的方法。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、胶质瘤和癌症，并可能有助于人类神经生物学和认知的进化发展。虽然到目前为止已经确定了许多RNA编辑站点，但我们距离拥有完整的RNA列表还很远 编辑目标，特别是在编码区，从而阻碍了对这一过程的复杂性及其治疗干预潜力的充分了解。我们建议将我们最近在开发实验和计算框架方面的成功扩展到生成人类和小鼠RNA编辑站点的全面地图集。通过结合多种经过验证的技术，我们将严格量化来自多个发育阶段的匹配的人和鼠组织的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，如黑猩猩和猕猴的RNA编辑，以期揭示RNA编辑对保守功能以及人类特有的神经进化的贡献。我们还将进行大规模的计算分析，以在带注释的基因组和转录组数据集中搜索与RNA编辑相关的功能元件。最后，我们建议使用各种突变的小鼠品系来解释RNA编辑的调节。综上所述，这一拟议项目的目标将加深我们对RNA编辑的分子基础的理解，产生一套实验和计算工具来推动RNA编辑领域的创新，并解开在时空上调节RNA编辑的信号网络，从而使我们更接近操纵RNA编辑以减轻人类疾病的目标。

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.