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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：
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编辑和修饰(构成表位转录组) 有助于转录组的多样性和灵活性。其中最常见的一种类型是腺苷到- 肌苷(A-to-I)，由作用于RNA的腺苷脱氨酶(ADAR)家族催化。 Adar与双链RNA(DsRNA)结合，并将特定的腺苷脱氨为肌苷，肌苷是被细胞机器读作鸟苷。ADAR的丢失导致一系列神经系统疾病在模式生物中证明的表型。RNA编辑级别的改变与神经性疾病的数量。RNA编辑的规则是非常动态的，在不同的组织，并处于不同的发育阶段。虽然我们之前由这笔赠款资助的工作导致了在组织水平上的动态调节的前所未有的视角，这些测量代表了编辑级别变化很大或基本相同的许多单元格的平均值。我们缺少一个好的了解不同细胞类型甚至单个细胞之间的RNA编辑差异有多大。特别是在神经元高度可塑性和存在多种细胞类型的大脑中，RNA编辑可能会在微调调节大脑功能和神经元连接的mRNA信息方面发挥作用在一生中。在这项工作中，我们旨在了解RNA编辑的动态调节前所未有的深度。首先，我们将分析苍蝇、小鼠、和人类。我们还将研究编辑在发展阶段和年中的变化在模式生物中对环境刺激的反应。第二，我们将分配RNA的功能利用高度自动化和灵敏的表型对果蝇不同神经回路的编辑化验。最后，为了机械地剖析动态规则，我们将对其进行识别和验证其他RNA编辑调节器，并确定这些调节器影响的机制在果蝇和哺乳动物中进行编辑。这项工作将提供对动态的更深入的理解不同神经细胞类型中A-to-I RNA编辑的调节以及RNA的作用在大脑功能中进行编辑。

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.

RNA编辑是常见炎症性疾病的遗传风险。

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