Dynamic regulation of N6-methyladenosine sites in neuronal RNAs

神经元 RNA 中 N6-甲基腺苷位点的动态调节

• 批准号: 8203366
• 负责人: Kathryn D Meyer
• 金额: $ 4.84万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-07-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8203366
• 关键词: Adenosine; Antibodies; Brain; Brain Diseases; Cell physiology; Consensus Sequence; Coupled; DNA; Deamination; Epigenetic Process; Event; Frequencies; Gene Expression Profile; Glutamates; Goals; Homologous Gene; Human; Immunoprecipitation; Individual; Knowledge; Lead; Location; Maps; Mediating; Messenger RNA; Methods; Methylation; Methyltransferase; Modification; Molecular; Nature; Neurons; Nucleosides; Organism; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Positioning Attribute; Post-Transcriptional RNA Processing; Process; Proteins; RNA; RNA Sequences; RNA Splicing; RNA methylation; Regulation; Research; Research Personnel; Role; Site; Site-Directed Mutagenesis; Specificity; Techniques; Testing; Translations; demethylation; design; insight; methyl group; mind control; nervous system disorder; novel; novel strategies; overexpression; research study; response; tool

DESCRIPTION (provided by applicant): Post-transcriptional modification of RNA occurs in all eukaryotic organisms and includes processes such as deamination, pseudouridinylation, and methylation. Such modifications are invaluable for RNA function, as they can influence processes ranging from RNA splicing to proper translation. Methylation at the N6 position of adenosine (N6-methyladenosine, or m6A) is the most prevalent methyl modification in mRNA, yet despite its abundance, it remains poorly understood. Although m6A is present at high levels in the brain, its influence on the function of neuronal RNAs is unknown. To investigate the role of m6A in brain function, the research proposed here will identify m6A targets susceptible to activity-dependent regulation within neurons using RNA-seq. In addition, this proposal will investigate potential methylation and demethylation pathways that regulate neuronal m6A abundance. These experiments will be the first to explore the dynamic regulation of the m6A modification within neurons on a transcriptome-wide level and will provide novel insights into how this highly prevalent modification contributes to neuron function. Furthermore, elucidating the intracellular pathways that influence m6A abundance will provide a better understanding of the mechanisms through which neuronal RNAs are regulated in response to neuronal activity. By determining the role that m6A plays in basic brain function, we can propel our understanding of the molecular and epigenetic events that contribute to brain disorders. PUBLIC HEALTH RELEVANCE: In neurons, the modification of RNAs is a dynamic process which has important consequences for brain function. The research proposed here will investigate the role of N6-methyladenosine (m6A), a particularly abundant RNA modification, in neuronal function. By identifying the neuronal RNAs containing m6A and the mechanisms controlling m6A abundance, we can gain important insights into how this highly prevalent modification contributes to basic brain function and how its disruption might lead to neurological disorders.

描述（由申请人提供）：RNA 的转录后修饰发生在所有真核生物中，包括脱氨、假尿苷酰化和甲基化等过程。这种修饰对于 RNA 功能来说是无价的，因为它们可以影响从 RNA 剪接到正确翻译的过程。腺苷 N6 位置的甲基化（N6-甲基腺苷，或 m6A）是 mRNA 中最常见的甲基化修饰，尽管其含量丰富，但人们对其仍知之甚少。尽管 m6A 在大脑中含量很高，但其对神经元 RNA 功能的影响尚不清楚。为了研究 m6A 在大脑功能中的作用，本文提出的研究将使用 RNA-seq 识别神经元内易受活动依赖性调节的 m6A 靶点。此外，该提案将研究调节神经元 m6A 丰度的潜在甲基化和去甲基化途径。这些实验将首次在转录组水平上探索神经元内 m6A 修饰的动态调节，并将为这种高度普遍的修饰如何促进神经元功能提供新的见解。此外，阐明影响 m6A 丰度的细胞内途径将有助于更好地理解神经元 RNA 响应神经元活动而受到调节的机制。通过确定 m6A 在基本大脑功能中发挥的作用，我们可以加深对导致大脑疾病的分子和表观遗传事件的理解。 公共卫生相关性：在神经元中，RNA 的修饰是一个动态过程，对大脑功能具有重要影响。这里提出的研究将调查 N6-甲基腺苷 (m6A)（一种特别丰富的 RNA 修饰）在神经元功能中的作用。通过鉴定含有 m6A 的神经元 RNA 以及控制 m6A 丰度的机制，我们可以获得重要的见解，了解这种高度普遍的修饰如何促进基本的大脑功能以及它的破坏如何可能导致神经系统疾病。