Post-transcriptional gene regulation by mRNA modifications

Abstract

N⁶-methyladenosine (m⁶A) is a prevalent post-transcriptional modification in mammalian mRNA. m⁶A is enriched in consensus sequences within long exons, near stop codons and at the 3′ untranslated regions (3′ UTRs). m⁶A is the first confirmed reversible mRNA modification with dedicated methyltransferases, demethylases and binding (effector) proteins. To date, four components of the m⁶A methyltransferase complex, two m⁶A demethylases and several m⁶A-binding proteins have been identified in mammals. m⁶A exerts its effects by directly recruiting effector proteins or by modulating RNA secondary structures, which modulate mRNA metabolism, including maturation, translation and decay. There is evidence to indicate that methylated transcripts can be sorted to synchronously fast track their metabolism. m⁶A has regulatory roles in many cellular processes, including circadian rhythm maintenance, stem cell differentiation and stress responses. m⁶A may facilitate cell-state transitions by regulating the metabolism of transcripts of key transcription factors. In addition to m⁶A, other modifications exist in mammalian mRNA, including N¹-methyladenosine (m¹A), 5-methylcytosine (m⁵C), pseudouridine and 2′-O-methylation (2′OMe). This collection of chemical modifications modulates nearly all aspects of RNA metabolism and related physiological processes, adding another layer to the already complex gene expression regulation pathways in eukaryotes, particularly in mammals.