Emerging Role of m⁶ A Methylome in Brain Development: Implications for Neurological Disorders and Potential Treatment

Dynamic modification of RNA affords proximal regulation of gene expression triggered by non-genomic or environmental changes. One such epitranscriptomic alteration in RNA metabolism is the installation of a methyl group on adenosine [N⁶-methyladenosine (m⁶A)] known to be the most prevalent modified state of messenger RNA (mRNA) in the mammalian cell. The methylation machinery responsible for the dynamic deposition and recognition of m⁶A on mRNA is composed of subunits that play specific roles, including reading, writing, and erasing of m⁶A marks on mRNA to influence gene expression. As a result, peculiar cellular perturbations have been linked to dysregulation of components of the mRNA methylation machinery or its cofactors. It is increasingly clear that neural tissues/cells, especially in the brain, make the most of m⁶A modification in maintaining normal morphology and function. Neurons in particular display dynamic distribution of m⁶A marks during development and in adulthood. Interestingly, such dynamic m⁶A patterns are responsive to external cues and experience. Specific disturbances in the neural m⁶A landscape lead to anomalous phenotypes, including aberrant stem/progenitor cell proliferation and differentiation, defective cell fate choices, and abnormal synaptogenesis. Such m⁶A-linked neural perturbations may singularly or together have implications for syndromic or non-syndromic neurological diseases, given that most RNAs in the brain are enriched with m⁶A tags. Here, we review the current perspectives on the m⁶A machinery and function, its role in brain development and possible association with brain disorders, and the prospects of applying the clustered regularly interspaced short palindromic repeats (CRISPR)-dCas13b system to obviate m⁶A-related neurological anomalies.