The dynamic epitranscriptome: N6-methyladenosine and gene expression control

Abstract

Two recent independent studies demonstrated that N⁶-methyladenosine (m⁶A) is a widespread base modification in the mammalian transcriptome, which exhibits a unique enrichment near the stop codon and in the untranslated regions (UTRs) of mRNAs. Recent studies have identified methyltransferase-like 3 (METTL3), METTL14 and Wilms tumour 1-associated protein (WTAP) as components of an m⁶A methyltransferase complex. Further characterization of this complex will be needed to understand the dynamics and specificity of adenosine methylation in various classes of cellular RNA. FTO (fat mass and obesity-associated protein) and ALKBH5 (α-ketoglutarate-dependent dioxygenase alkB homologue 5) are the two m⁶A demethylating enzymes identified to date. Based on studies of the mRNA targeting specificity and tissue-specific expression patterns of these enzymes, however, it is likely that additional m⁶A demethylases exist. m⁶A probably functions by recruiting m⁶A binding proteins, which influence RNA processing and regulation. Although a small number of m⁶A-binding proteins have been identified, much work remains to understand the full repertoire of m⁶A-binding proteins and how they contribute to mRNA regulation. Although m⁶A probably has many functions, studies so far suggest that it has a role in splicing regulation and mRNA stability.