Dynamic regulation of N6,2′-O-dimethyladenosine (m6Am) in obesity

The prevalent m 6 Am mRNA cap modification was recently identified as a valid target for removal by the human obesity gene FTO along with the previously established m 6 A mRNA modification. However, the deposition and dynamics of m 6 Am in regulating obesity are unknown. Here, we investigate the liver m 6 A/m methylomes in mice fed on a high fat Western-diet and in ob/ob mice. We find that FTO levels are elevated in fat mice, and that genes which lost m 6 Am marking under obesity are overly downregulated, including the two fatty-acid-binding proteins FABP2, and FABP5. Furthermore, the cellular perturbation of FTO correspondingly affect protein levels of its targets. Notably, generally m 6 Am- but not m 6 A-methylated genes, are found to be highly enriched in metabolic processes. Finally, we deplete all m 6 A background via Mettl3 knockout, and unequivocally uncover the association of m 6 Am methylation with increased mRNA stability, translation efficiency, and higher protein expression. Together, these results strongly implicate a dynamic role for m 6 Am in obesity-related translation regulation. m6A and m6Am are two prevalent mRNA modifications which are target for removal by the fat mass and obesity gene FTO. Here the authors capture the differential profile of these two modifications in the liver of obese mice and identify dynamic translation regulation by the m6Am modification.