The cap epitranscriptome: Early directions to a complex life as mRNA

Animal, protist and viral messenger RNAs (mRNAs) are most prominently modified at the beginning by methylation of cap-adjacent nucleotides at the 2′-O-position of the ribose (cOMe) by dedicated cap methyltransferases (CMTrs). If the first nucleotide of an mRNA is an adenosine, PCIF1 can methylate at the N⁶-position (m⁶A), while internally the Mettl3/14 writer complex can methylate. These modifications are introduced co-transcriptionally to affect many aspects of gene expression including localisation to synapses and local translation. Of particular interest, transcription start sites of many genes are heterogeneous leading to sequence diversity at the beginning of mRNAs, which together with cOMe and m⁶Am could constitute an extensive novel layer of gene expression control. Given the role of cOMe and m⁶A in local gene expression at synapses and higher brain functions including learning and memory, such code could be implemented at the transcriptional level for lasting memories through local gene expression at synapses.