m⁶ A RNA methylation: from mechanisms to therapeutic potential

RNA carries a diverse array of chemical modifications that play important roles in the regulation of gene expression. N⁶ -methyladenosine (m⁶ A), installed onto mRNA by the METTL3/METTL14 methyltransferase complex, is the most prevalent mRNA modification. m⁶ A methylation regulates gene expression by influencing numerous aspects of mRNA metabolism, including pre-mRNA processing, nuclear export, decay, and translation. The importance of m⁶ A methylation as a mode of post-transcriptional gene expression regulation is evident in the crucial roles m⁶ A-mediated gene regulation plays in numerous physiological and pathophysiological processes. Here, we review current knowledge on the mechanisms by which m⁶ A exerts its functions and discuss recent advances that underscore the multifaceted role of m⁶ A in the regulation of gene expression. We highlight advances in our understanding of the regulation of m⁶ A deposition on mRNA and its context-dependent effects on mRNA decay and translation, the role of m⁶ A methylation of non-coding chromosomal-associated RNA species in regulating transcription, and the activities of the RNA demethylase FTO on diverse substrates. We also discuss emerging evidence for the therapeutic potential of targeting m⁶ A regulators in disease.