Epitranscriptomic regulation by m6A RNA methylation in brain development and diseases

Cellular RNAs are pervasively tagged with diverse chemical moieties, collectively called epitranscriptomic modifications. The methylation of adenosine at N-6 position generates N-6-methyladenosine (m(6)A), which is the most abundant and reversible epitranscriptomic modification in mammals. The m(6)A signaling is mediated by a dedicated set of proteins comprised of writers, erasers, and readers. Contrary to the activation-repression binary view of gene regulation, emerging evidence suggests that the m(6)A methylation controls multiple aspects of mRNA metabolism, such as splicing, export, stability, translation, and degradation, culminating in the fine-tuning of gene expression. Brain shows the highest abundance of m(6)A methylation in the body, which is developmentally altered. Within the brain, m(6)A methylation is biased toward neuronal transcripts and sensitive to neuronal activity. In a healthy brain, m(6)A maintains several developmental and physiological processes such as neurogenesis, axonal growth, synaptic plasticity, circadian rhythm, cognitive function, and stress response. The m(6)A imbalance contributes to the pathogenesis of acute and chronic CNS insults, brain cancer, and neuropsychiatric disorders. This review discussed the molecular mechanisms of m(6)A regulation and its implication in the developmental, physiological, and pathological processes of the brain.