Implications of Widespread Covalent Modification of mRNA

Whole transcriptome analysis reveals that one third of human and mouse genes express mRNAs containing methylated adenosines. Fat mass and obesity-associated ( FTO ) gene, a risk gene for obesity and metabolic abnormalities, demethylates the modified residues, suggesting a link between RNA methylation and disease. Vertebrate ribosomal RNA (rRNA), transfer RNA (tRNA), messenger RNAs (mRNAs) as well as viral RNAs can be methylated at the N6 position of adenosines to produce N6-methyladenosine (m6A). Although the presence of m6A modifications in mRNA has been known for decades and a handful of vertebrate m6A-modified mRNAs have been identified, the extent of m6A modification in mRNAs was unknown. Two recent articles using massively parallel sequencing found that mRNAs from more than one third of human and mouse genes contain m6A.1,2 N6-methyladenosines were found to be enriched near the translational stop codon, as well as in mRNA segments derived from large exons. Furthermore, the results showed that the genes modified and the distribution of modifications within mRNAs is conserved between mouse and humans. Particularly intriguing is the recent discovery that FTO gene, a risk gene for obesity and metabolic abnormalities, is an m6A demethylase. These results suggest a potential regulatory role for covalent modification of RNA and a link with metabolic disorders.Over the past 2 decades, RNA has been revealed as one of the most functionally diverse and information-rich molecules in the cell.3 RNA can function as a viral genome, message, decoding machine, guide to target proteins, enzyme, template and primer for DNA synthesis, and structural component. RNA carries information as primary nucleotide sequence and by using a huge structural space to provide a fit for diverse molecular interactions. Pre-mRNAs transcribed by RNA polymerase II are extensively modified and processed into mature mRNA by addition of the 5′ cap, splicing, and …