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.
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.
| Meyer, Kate D; Saletore, Yogesh; Zumbo, Paul et al. (2012) Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons. Cell 149:1635-46 |
