mRNA Methylation: a Novel Regulatory Mechanism in the Neuronal Transcriptome

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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.