Dynamic regulation of N(6),2′-O-dimethyladenosine (m(6)Am) 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.