Systematic approaches to deciphering regulation and function of RNA editing in brain

项目摘要 测序技术和生物信息学方法的最新进展使 在更好地理解RNA的加工、调节和修饰方面取得了很大进展。核糖核酸 编辑是一种流行的RNA修饰类型，其中RNA序列通过 核苷酸的插入、缺失或替换。在哺乳动物中，最常见的RNA类型 编辑是腺苷到肌苷(A对I)的编辑。A-to-I编辑对于正常生活和 发展。发现了一些A-to-I编辑网站，它们在 神经元信号，通过调节膜兴奋性、神经传递可塑性和信号 转导。此外，异常的RNA编辑与人类神经精神疾病有关 疾病，如自闭症、阿尔茨海默病、抑郁症、精神分裂症和肌营养不良 侧索硬化症。虽然通过RNA测序已经确定了大量的RNA编辑位点 (rna-seq)和相关技术，在理解其功能和 RNA编辑的调控。已知的绝大多数人类RNA编辑站点位于非 编码区，如内含子和非翻译区，可赋予调节功能 相关基因，尤其是在转录后调控水平上。因此，有一个 迫切需要深入研究RNA编辑对后处理的功能影响 转录调控。RNA编辑的调节机制还没有得到很好的描述。 除了ADAR酶，很少有蛋白质及其作用机制被研究过。 用于RNA编辑。一个主要的挑战是缺乏有效和系统的方法来确定 新奇的监管者。在这个项目中，我们计划扩展我们最近在开发 解决上述挑战的生物信息学和实验框架。我们将利用这一点 关于从死后大脑样本中提取的大量rna-seq数据集。我们会 开发和应用新的方法以充分利用这些数据集，并辅之以 进一步的生物信息学预测和高通量实验测试，以预测和验证 RNA编辑的分子功能及相关调控机制。这项工作将允许 对RNA编辑的分子基础的了解达到了前所未有的水平，并提供了 对RNA编辑参与人类生物学的新见解。

Project Summary Recent advances in sequencing technologies and bioinformatic methodologies have enabled great progress in better understanding RNA processing, regulation and modification. RNA editing is a prevalent type of RNA modification where the RNA sequences are altered through insertion, deletion or substitution of nucleotides. In mammals, the most common type of RNA editing is adenosine to inosine (A-to-I) editing. A-to-I editing is essential for normal life and development. A handful of A-to-I editing sites have been discovered with critical roles in neuronal signaling, by modulating membrane excitability, neurotransmission plasticity and signal transduction. In addition, aberrant RNA editing has been implicated in human neuropsychiatric diseases, such as Autism, Alzheimer’s disease, depression, schizophrenia, and amyotrophic lateral sclerosis. While numerous RNA editing sites have been identified via RNA-sequencing (RNA-seq) and related technologies, major challenges exist in understanding the function and regulation of RNA editing. The vast majority of known human RNA editing sites reside in non- coding regions, such as introns and untranslated regions, that may confer regulatory function to the related gene, especially at the level of post-transcriptional regulation. Therefore, there is a great demand for in-depth studies of the functional impacts of RNA editing on post- transcriptional regulation. The regulatory mechanisms of RNA editing are poorly characterized. Except the ADAR enzymes, few proteins and their mechanisms of action have been examined for RNA editing. A major challenge is the lack of efficient and systematic methods to pinpoint novel regulators. In this project, we propose to extend our recent success at developing bioinformatic and experimental frameworks to address the above challenges. We will capitalize on the large collection of RNA-seq data sets derived from postmortem brain samples. We will develop and apply novel methodologies to make full use of these data sets, complemented by further bioinformatic prediction and high-throughput experimental testing, to predict and validate the molecular function of RNA editing and related regulatory mechanisms. This work will allow a previously unattained level of understanding of the molecular basis of RNA editing and provide new insights to the involvement of RNA editing in human biology.