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Base-resolution mapping and site-specific epitranscriptomic studies in the brain

大脑中的碱基分辨率图谱和位点特异性表观转录组学研究

基本信息

批准号：
10024089
负责人：
Bryan Dickinson
金额：
$ 46.99万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-25 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10024089
关键词：
Adenosine Adult Affect Antibodies Base Pairing Binding Proteins Brain Brain region Catalogs Charge Chemicals Clinical Communities Complex Data Data Set Detection Development Disease Engineering Event Evolution Foundations Future Gene Expression Genetic Transcription Guide RNA Impairment Individual Investigation Learning Logic Mammals Memory Mental disorders Messenger RNA Methods Methylation Methyltransferase Modeling Modification Molecular Mutation Neurobiology Neurons Organ Pathologic Pathology Physiological Play Population Post-Translational Protein Processing Prevalence Probability Process Protein Biosynthesis Proteins RNA RNA delivery RNA metabolism RNA-Binding Proteins RNA-Directed DNA Polymerase Reader Research Resolution Role Sample Size Sampling Services Site Structure Synapses Synaptic plasticity Synaptosomes System Techniques Technology Testing Tissues Transcript Transcriptional Regulation Translations Validation Work base brain abnormalities cell type design epitranscriptome epitranscriptomics experimental study in vivo innovative technologies insight methylome neurodevelopment neuronal cell body new technology prevent programs recruit response tool trafficking transcription factor

项目摘要

PROJECT SUMMARY Both neurodevelopment and the synaptic plasticity events that underlie learning and memory rely heavily on tightly regulated gene expression programs and rapid, finely-tuned translation of messenger RNA (mRNA) transcripts. The degradation, stability, and translation of mRNA has, in recent years, been found to be regulated by adenosine methylation, which alters both transcript structure and the recruitment of RNA-binding proteins that inform these activities. Recent identification of and experimentation with the methyltransferases (“writers”), demethylases (“erasers”), and specific methyladenosine binding proteins (“readers”) have established that these epitranscriptomic mRNA regulatory processes are both dynamic and tightly regulated. Although the most well-studied of these modifications is N6-methyladenosine (m6A), N1- methyladenosine (m1A) has also recently emerged as a prevalent epitranscriptomic mark. Current methods used to explore these modifications require large sample sizes and are inherently low-resolution. These limitations preclude them from mapping and quantifying the epitranscriptome in specific brain regions, or in clinical biospecimens. Here, we describe preliminary development of innovative technologies to precisely sequence and probe the function of specific m6A and m1A modifications. We propose to leverage these foundations in the service of the following specific aims: 1) Evolve and establish high-resolution, antibody-free m6A and m1A mapping platforms for brain analysis, 2) Design and validate a molecular toolkit to manipulate transcript-specific m6A and m1A modifications in vivo, and 3) Catalog m6A and m1A modifications in the brain across development, neuron populations, activity state, and in synapses, and determine their function in relation to learning and memory. Our findings will illuminate how the epitranscriptomic landscape and specific mRNA transcripts in discrete neuronal populations regulates gene expression to inform complex neuronal processes, such as development, learning and memory, and how perturbations thereof result in abnormal brain function such as learning impairment. Importantly, this translational, functional validation of our new tools, which will be made available to the research community, provides a strong foundation for their usage to specifically interrogate how mRNA modifications are perturbed in other pathological contexts.

项目总结