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Profiling and Dissecting the Dynamic Regulation of RNA Editing

分析和剖析 RNA 编辑的动态调控

基本信息

批准号：
9524273
负责人：
Jin Billy Li
金额：
$ 30.63万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9524273
关键词：
Adenosine Affinity Chromatography Animal Model Behavior Biological Assay Brain Cell Nucleus Cells Data Development Disease Double-Stranded RNA Drosophila And protein Drosophila genus Embryo Enzymes Event Family Funding Future Genetic Genetic Transcription Goals Grant Guanosine Human Inosine Knowledge Life Light Link Locomotion Mammals Measurement Measures Messenger RNA Microfluidics Modification Molecular Mus Mutation Neurologic Neurons Organism Pharmacology Phenotype Play Process Progress Reports Protein Isoforms Protocols documentation Publications RNA RNA Binding RNA Editing RNA Interference RNA-Binding Proteins Regulation Ribosomes Role Sampling Site Social Behavior Stimulus System Techniques Therapeutic Tissues Translating Work adenosine deaminase base cell type data resource epitranscriptome flexibility fly human disease in vivo innovation innovative technologies insight knock-down nervous system disorder neural circuit neuronal circuitry novel novel strategies response single-cell RNA sequencing spatiotemporal transcriptome

项目摘要

The remarkably prevalent RNA editing and modifications (which constitute the epitranscriptome) contribute to transcriptome diversity and flexibility. One of the most common types is adenosine-to- inosine (A-to-I), catalyzed by the adenosine deaminase acting on RNA (ADAR) family of enzymes. ADAR binds to double-stranded RNA (dsRNA) and deaminates specific adenosine to inosine, which is read as guanosine by the cellular machinery. Loss of ADAR leads to a range of neurological phenotypes as demonstrated in model organisms. Alteration of RNA editing levels is associated with a number of neurological disorders. The regulation of RNA editing is very dynamic, varying in different tissues and at different developmental stages. While our previous work funded by this grant led to an unprecedented view of dynamic regulation at the tissue level, the measurements represent an average of many cells with widely variable or largely equal editing levels. We lack a good understanding of how much RNA editing varies between different cell types or even single cells. Particularly in the brain, where neurons are highly plastic and many cell types exist, RNA editing may play a role in fine-tuning mRNA messages that modulate brain function and neuronal connectivity throughout life. In this work, we aim to understand the dynamic regulation of RNA editing at an unprecedented depth. First, we will profile RNA editing in different neuronal cell types in flies, mice, and humans. We will also examine the changes of editing during developmental stages and in response to environmental stimuli in model organisms. Second, we will assign functions of RNA editing in different neural circuits in Drosophila using a highly automated and sensitive phenotypic assay. Finally, to mechanistically dissect the dynamic regulation, we will identify and validate additional RNA editing regulators and determine the mechanisms by which these regulators influence editing in Drosophila and mammals. This work will provide a deeper understanding of the dynamic regulation of A-to-I RNA editing in different neuronal cell types and shed light on the role of RNA editing in brain function.

非常普遍的 RNA 编辑和修饰（构成表观转录组）有助于转录组的多样性和灵活性。最常见的类型之一是腺苷- 肌苷（A-to-I），由作用于 RNA (ADAR) 家族酶的腺苷脱氨酶催化。 ADAR 与双链 RNA (dsRNA) 结合并将特定腺苷脱氨为肌苷，这是被细胞机器读取为鸟苷。 ADAR 的丧失会导致一系列神经系统疾病模型生物中所展示的表型。 RNA 编辑水平的改变与神经系统疾病的数量。 RNA编辑的调控是非常动态的，在不同的环境中存在差异。组织和不同发育阶段。虽然我们之前由这笔赠款资助的工作导致了组织水平动态调节的前所未有的观点，测量代表了许多编辑水平差异很大或基本相同的单元格的平均值。我们缺少一个好的了解不同细胞类型甚至单个细胞之间 RNA 编辑的差异程度。特别是在大脑中，神经元具有高度可塑性并且存在多种细胞类型，RNA 编辑可能在微调 mRNA 信息中发挥作用，调节大脑功能和神经元连接一生。在这项工作中，我们的目标是了解 RNA 编辑的动态调控前所未有的深度。首先，我们将分析果蝇、小鼠等不同神经元细胞类型中的 RNA 编辑情况。和人类。我们还将研究编辑在发展阶段和过程中的变化。模型生物对环境刺激的反应。其次，我们将分配RNA的功能使用高度自动化和敏感的表型编辑果蝇的不同神经回路化验。最后，为了机械地剖析动态调节，我们将识别并验证其他 RNA 编辑调节因子并确定这些调节因子影响的机制果蝇和哺乳动物的编辑。这项工作将提供对动态的更深入的理解不同神经元细胞类型中 A 到 I RNA 编辑的调节并揭示 RNA 的作用编辑大脑功能。