Epitranscriptomic regulation by m6A RNA methylation in brain development and diseases

Abstract

Cellular RNAs are pervasively tagged with diverse chemical moieties, collectively called epitranscriptomic modifications. The methylation of adenosine at N6 position generates N6-methyladenosine (m6A), which is the most abundant and reversible epitranscriptomic modification in mammals. The m6A 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 m6A 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 m6A methylation in the body, which is developmentally altered. Within the brain, m6A methylation is biased toward neuronal transcripts and sensitive to neuronal activity. In a healthy brain, m6A maintains several developmental and physiological processes such as neurogenesis, axonal growth, synaptic plasticity, circadian rhythm, cognitive function, and stress response. The m6A imbalance contributes to the pathogenesis of acute and chronic CNS insults, brain cancer, and neuropsychiatric disorders. This review discussed the molecular mechanisms of m6A regulation and its implication in the developmental, physiological, and pathological processes of the brain.