N6-methyladenosine



N6-methyladenosine (m6A) is an abundant modification in mRNA, and also in long non-coding RNA, such as MALAT1. It is installed by a large m6A methyltransferase complexes containing METTL3 as the SAM-binding sub-unit. Mapping of m6A in human and mouse RNA have identify over 12,000 m6A sites characterized by a typical consensus in the transcripts of more than 7,000 human genes with consensus sequence of [G/A/U][G>A]m6AC[U>A/C]. Sites preferentially appear in two distinct landmarks—around stop codons and within long internal exons—and are highly conserved between human and mouse. A subset of stimulus-dependent, dynamically modulated sites has been identified. Silencing the m6A methyltransferase significantly affects gene expression and alternative RNA splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. RNA decoration by m6A has a fundamental role in regulation of gene expression. FTO gene is shown to demethylate m6A in RNA. FTO gene knockdown with siRNA led to increased amounts of m6A in polyA-RNA, whereas overexpression of FTO gene resulted in decreased amounts of m6A in human cells. FTO partially co-localizes with nuclear speckles, which supports the notion that m6A in nuclear RNA is a major physiological substrate of FTO. Function of FTO gene likely affects the processing of pre-mRNA, other nuclear RNAs, or both. The discovery of the FTO-mediated oxidative demethylation of m6A in nuclear RNA may initiate further investigations on biological regulation based on reversible chemical modification of RNA.