Genomics of RNA Editing: Identification and Regulation

描述（由申请人提供）：通过人类基因组计划和其他大规模调查的努力，已经清楚的是，人类复杂性，疾病和与其他生物体的差异性的分子起源不仅仅植根于基因组中基因的数量。RNA编辑是通过对单个RNA碱基进行化学修饰来改变基因组编码信息的转录后改变，它提供了一种潜在的强有力的方式来使生物体组织中表达的RNA组随着时间的推移而多样化。异常RNA编辑与人类神经系统疾病如肌萎缩性侧索硬化症、癫痫、抑郁症、自杀、神经胶质瘤和癌症有关，并可能有助于人类神经生物学和认知的进化发展。尽管迄今为止已经鉴定出了许多RNA编辑位点，但我们仍然远远没有拥有一个完整的RNA编辑位点列表。 编辑目标，特别是在编码区，从而阻碍了充分理解这一过程的复杂性及其潜在的治疗干预。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中RNA编辑位点的综合图谱。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匹配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（如黑猩猩和恒河猴）的RNA编辑，以期揭示RNA编辑对保守功能以及人类特异性神经进化的贡献。我们还将进行大规模的计算分析，以在注释的基因组和转录组数据集中搜索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进行RNA编辑的酶来阐明RNA编辑的调节。总的来说，这个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，并解开时空调节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.