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：
10228696
负责人：
Jin Billy Li
金额：
$ 29.47万
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/10228696
关键词：
Adenosine Affinity Chromatography Animal Model Behavior Biological Assay Brain Cell Nucleus Cells Data Development Disease Double-Stranded RNA 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 behavioral phenotyping 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编辑和修改（构成表面翻译组）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至肌苷（A-to-I），由作用于RNA（ADAR）酶家族的腺苷脱氨酶催化。 ADAR与双链RNA（DSRNA）结合，并将特定的腺苷脱离至肌苷，即通过细胞机械读取为鸟氨酸。失去ADAR会导致一系列神经系统模型生物中所示的表型。 RNA编辑水平的改变与神经系统疾病的数量。 RNA编辑的调节非常动态，不同组织和不同的发育阶段。虽然我们以前由这笔赠款资助的工作导致了在组织水平上动态调节的前所未有的观点，测量代表许多具有广泛可变或大量相等编辑水平的单元的平均值。我们缺乏好了解不同细胞类型甚至单个细胞之间的RNA编辑多少不同。特别是在神经元高度塑性且存在许多细胞类型的大脑中，RNA编辑可能在调节大脑功能和神经元连接性的微调mRNA消息中发挥作用一生。在这项工作中，我们旨在了解RNA编辑的动态调节空前的深度。首先，我们将在蝇，小鼠中的不同神经元细胞类型中介绍RNA编辑和人类。我们还将检查在发育阶段和中的编辑变化模型生物中对环境刺激的反应。其次，我们将分配RNA的功能使用高度自动化和敏感的表型在果蝇中的不同神经回路中进行编辑测定。最后，要机械剖析动态调节，我们将识别并验证其他RNA编辑调节器并确定这些调节器影响的机制果蝇和哺乳动物的编辑。这项工作将为动态提供更深入的了解调节不同神经元细胞类型中A到I RNA编辑，并阐明RNA的作用大脑功能的编辑。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of human RNA editing sites: A historical perspective.

DOI：
10.1016/j.ymeth.2016.05.011
发表时间：
2016-09-01
期刊：
METHODS
影响因子：
4.8
作者：
Ramaswami, Gokul;Li, Jin Billy
通讯作者：
Li, Jin Billy

Protein recoding by ADAR1-mediated RNA editing is not essential for normal development and homeostasis.

DOI：
10.1186/s13059-017-1301-4
发表时间：
2017-09-05
期刊：
Genome biology
影响因子：
12.3
作者：
Heraud-Farlow JE;Chalk AM;Linder SE;Li Q;Taylor S;White JM;Pang L;Liddicoat BJ;Gupte A;Li JB;Walkley CR
通讯作者：
Walkley CR

Zinc Finger RNA-Binding Protein Zn72D Regulates ADAR-Mediated RNA Editing in Neurons.

锌指 RNA 结合蛋白 Zn72D 调节神经元中 ADAR 介导的 RNA 编辑。

DOI：
10.1016/j.celrep.2020.107654
发表时间：
2020
期刊：
Cell reports
影响因子：
8.8
作者：
Sapiro,AnneL;Freund,EmilyC;Restrepo,Lucas;Qiao,Huan-Huan;Bhate,Amruta;Li,Qin;Ni,Jian-Quan;Mosca,TimothyJ;Li,JinBilly
通讯作者：
Li,JinBilly

Efficient and precise editing of endogenous transcripts with SNAP-tagged ADARs.

DOI：
10.1038/s41592-018-0017-z
发表时间：
2018-07
期刊：
Nature methods
影响因子：
48
作者：
Vogel P;Moschref M;Li Q;Merkle T;Selvasaravanan KD;Li JB;Stafforst T
通讯作者：
Stafforst T

RNA editing underlies genetic risk of common inflammatory diseases.

DOI：
10.1038/s41586-022-05052-x
发表时间：
2022-08
期刊：
NATURE
影响因子：
64.8
作者：
Li, Qin;Gloudemans, Michael J.;Geisinger, Jonathan M.;Fan, Boming;Aguet, Francois;Sun, Tao;Ramaswami, Gokul;Li, Yang, I;Ma, Jin-Biao;Pritchard, Jonathan K.;Montgomery, Stephen B.;Li, Jin Billy
通讯作者：
Li, Jin Billy