Mechanistic Insights into m6A-Mediated Regulation of Brain Development

m6A 介导的大脑发育调节的机制见解

基本信息

批准号：
10295195
负责人：
Kathryn D Meyer
金额：
$ 39.48万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-10 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10295195
关键词：
3&apos Untranslated Regions Adenosine Affinity Binding Binding Proteins Biochemical Brain Cell Culture Techniques Cell Differentiation process Cell Line Cell Proliferation Coupled Defect Deposition Development Disease Embryo Enzymes Event Fishes Future Gene Expression Gene Expression Profiling Gene Targeting Genetic Translation Goals Health Human In Vitro Lead Mediating Messenger RNA Methylation Methyltransferase Modeling Modification Multiprotein Complexes Mus Nervous System Physiology Neuroglia Neurons Nucleotides Pathway interactions Play Prevalence Process Property Protein Family Proteins RNA RNA Binding RNA Splicing RNA-Binding Proteins Reader Regulation Regulatory Pathway Research Research Personnel Resolution Role Site Specificity Terminator Codon Tissues Transcription Process Translations base cell type epitranscriptomics experimental study fly in vivo insight interdisciplinary approach mRNA Export mRNA Stability nerve stem cell nervous system disorder neurodevelopment neurogenesis novel protein complex recruit response stem cell differentiation stem cell proliferation transcriptome

项目摘要

ABSTRACT N6-methyladenosine, or m6A, is a highly abundant base modification which was recently shown to be present in thousands of cellular mRNAs. Many of the functional roles of this mark are carried out by m6A-binding proteins, or “readers”, which bind m6A residues and contribute to various aspects of mRNA regulation, including mRNA export, stability, and translation. Depletion of the methyltransferase enzymes that catalyze m6A formation has been shown to disrupt stem cell proliferation and differentiation and to lead to developmental defects. In the brain, where m6A is particularly abundant, m6A depletion has been shown to disrupt neurogenesis and cause severe neurodevelopmental abnormalities. However, the mechanisms through which m6A regulates gene expression to control neurodevelopmental processes are poorly understood. In addition, the proteins mediating m6A function in the developing brain have not been explored. Here, we will investigate the function of a previously unknown m6A binding protein during brain development. First, we will uncover the key features that determine m6A binding specificity. Second, we will utilize m6A-depleted neuronal cell lines coupled with transcriptome-wide RNA binding studies to uncover the cellular mRNAs that are targeted by this reader through m6A. Third, we will use a combination of global gene expression profiling and gene targeting approaches to determine how m6A:reader interactions contribute to gene expression changes and neurodevelopment. Collectively, these studies will characterize a novel m6A reader in the brain and will provide important mechanistic insight into how m6A regulates brain development.

抽象的 N6-甲基腺苷，或 m6A，是一种高度丰富的碱基修饰，最近被证明存在于该标记的许多功能作用是由 m6A 结合蛋白执行的。或“阅读器”，它结合 m6A 残基并有助于 mRNA 调节的各个方面，包括 mRNA 催化 m6A 形成的甲基转移酶的消耗已被证明会破坏干细胞增殖和分化并导致发育缺陷。大脑中 m6A 特别丰富，m6A 耗竭已被证明会破坏神经发生并导致然而，m6A 调节基因的机制。此外，人们对控制神经发育过程的表达知之甚少。 m6A 在发育中的大脑中的功能尚未被探索过，在此，我们将研究先前的 m6A 功能。首先，我们将揭示大脑发育过程中未知的 m6A 结合蛋白。其次，我们将利用 m6A 耗尽的神经元细胞系与全转录组结合。 RNA 结合研究以揭示该读取器通过 m6A 靶向的细胞 mRNA 第三，我们将。结合使用全局基因表达谱和基因靶向方法来确定如何 m6A：读者互动有助于基因表达变化和神经发育。研究将描述大脑中新型 m6A 阅读器的特征，并将提供重要的机制见解 m6A 调节大脑发育。