Emerging Role of m(6) 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 [N(6)-methyladenosine (m(6)A)] 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 m(6)A on mRNA is composed of subunits that play specific roles, including reading, writing, and erasing of m(6)A 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 m(6)A modification in maintaining normal morphology and function. Neurons in particular display dynamic distribution of m(6)A marks during development and in adulthood. Interestingly, such dynamic m(6)A patterns are responsive to external cues and experience. Specific disturbances in the neural m(6)A landscape lead to anomalous phenotypes, including aberrant stem/progenitor cell proliferation and differentiation, defective cell fate choices, and abnormal synaptogenesis. Such m(6)A-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 m(6)A tags. Here, we review the current perspectives on the m(6)A 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 m(6)A-related neurological anomalies.