mRNA Methylation: a Novel Regulatory Mechanism in the Neuronal Transcriptome

mRNA 甲基化：神经元转录组中的一种新型调控机制

• 批准号: 8767326
• 负责人: Kathryn D Meyer
• 金额: $ 9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-18 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8767326
• 关键词: 5' Untranslated Regions; Adenosine; Affinity; Antibodies; Area; Award; Biochemical; Bioinformatics; Brain; Cells; Chemicals; Computer Analysis; Cytosine; DNA; Data Set; Development; Disease; Epigenetic Process; Event; Exhibits; Gene Expression; Gene Expression Profile; Generations; Genetic Translation; Goals; Grant; High Prevalence; Immunoprecipitation; Individual; Knowledge; Label; Laboratory Study; Lead; Location; Maps; Mediating; Mental Health; Mentors; Messenger RNA; Methods; Methylation; Methyltransferase; Modification; Molecular; Molecular Neurobiology; Mutate; Neurons; Nucleotides; Paper; Phase; Play; Positioning Attribute; Prevalence; Production; Proteins; Psyche structure; Publishing; RNA; Regulation; Regulatory Pathway; Research; Research Personnel; Resolution; Ribosomes; Role; Running; Scientist; Site; Specificity; Techniques; Terminator Codon; Testing; Time; Tissues; Training; Transcript; Translating; Translation Initiation; Translational Regulation; Translations; Untranslated Regions; Writing; base; career; computer program; design; innovation; insight; neurodevelopment; next generation sequencing; novel; public health relevance; research study; skills; tool

DESCRIPTION (provided by applicant): This project is designed to enhance the skills, knowledge, and scientific training of Dr. Kate Meyer as she transitions into a career as an independent research scientist. Dr. Meyer recently published a landmark study in which she showed for the first time that N6-methyladenosine (m6A) is a widespread, reversible base modification in mRNA. m6A exhibits a unique distribution within mRNAs, with the most highly enriched regions being near the stop codon and in the 5'UTR. Additionally, Dr. Meyer discovered that m6A is particularly abundant within the brain and that its levels increase steadily throughout neurodevelopment. This suggests that mRNA methylation is a widespread mechanism of neuronal mRNA regulation which contributes to brain development and function. However, despite the prevalence of m6A within the brain and its potential to influence a substantial portion of the neuronal transcriptome, its function remains unknown. The research proposed here will utilize a combination of technically and conceptually innovative approaches to investigate the localization, regulation, and function of m6A in neuronal mRNAs. In Aim 1, Dr. Meyer will develop a new tool for globally detecting m6A residues at single-nucleotide resolution and will identify the neuronal mRNAs which are dynamically methylated during brain development. Aim 2 will utilize a combination of biochemical experiments and m6A mapping techniques to determine the factors that control m6A localization in neuronal mRNAs. These experiments will help answer the long-standing question of how adenosine methylation is directed to particular regions of a transcript. Finally, Aim 3 will explore the role of m6A in regulating neuronal mRNA translation. The results of these experiments will provide important insight into how m6A contributes to basic brain function and will propel our understanding of the molecular and epigenetic events that contribute to mental health and disease. To achieve these research goals, Dr. Meyer will receive extensive training in computer programming and bioinformatic analysis. This new skill set will be invaluable for Dr. Meyer to have, since many of her studies as an independent researcher in the field of molecular neurobiology will involve the generation and analysis of large next- generation sequencing datasets. In addition to enabling Dr. Meyer to develop expertise in computational analysis, this award will further enhance her skills in grant writing, mentoring, and other key areas which are crucial for a successful career as an independent research scientist. Thus, by the end of the mentored phase of this award, Dr. Meyer will be in an ideal position to achieve her long-term career goal of running a successful research laboratory studying mRNA methylation and its role in mental health and disease.

描述（由申请人提供）：该项目旨在提高凯特·迈耶（Kate Meyer）博士的技能，知识和科学培训，因为她过渡为独立研究科学家的职业。 Meyer博士最近发表了一项具有里程碑意义的研究，她首次表明N6-甲基丙氨酸（M6A）是mRNA中广泛的，可逆的基础修饰。 M6A在mRNA中表现出独特的分布，其中最丰富的地区在终止密码子附近和5'UTR中。此外，迈耶博士发现，M6A在大脑中特别丰富，其水平稳定增加 整个神经发育。这表明mRNA甲基化是神经元mRNA调节的广泛机制，有助于脑发育和功能。然而，尽管M6A在大脑内的流行率及其影响神经元转录组的大部分的潜力，但其功能仍然未知。这里提出的研究将利用技术和概念创新方法的结合来研究M6A在神经元mRNA中的定位，调节和功能。在AIM 1中，Meyer博士将开发一种新工具，用于在单核苷酸分辨率下全球检测M6A残基，并将鉴定在大脑发育过程中动态甲基化的神经元mRNA。 AIM 2将利用生化实验和M6A映射技术的组合来确定控制神经元mRNA中M6A定位的因素。这些实验将有助于回答一个长期存在的问题，即腺苷甲基化如何针对转录本的特定区域。最后，AIM 3将探讨M6A在调节神经元mRNA翻译中的作用。这些实验的结果将为M6A如何促进基本脑功能的贡献，并推动我们对有助于心理健康和疾病的分子和表观遗传事件的理解。为了实现这些研究目标，迈耶博士将接受计算机编程和生物信息学分析的广泛培训。迈耶博士拥有这个新技能将是无价的，因为她作为分子神经生物学领域的独立研究人员的许多研究将涉及对大型下一代测序数据集的生成和分析。除了使Meyer博士能够在计算分析方面发展专业知识外，该奖项还将进一步提高她在赠款写作，指导和其他关键领域的技能，这对于成功作为独立研究科学家的职业至关重要。因此，到该奖项的指导阶段结束时，迈耶博士将有理想的位置，可以实现她的长期职业目标，即成功地研究MRNA甲基化及其在心理健康和疾病中的作用。