Dynamic Regulation of N6 ,2′-O-dimethyladenosine (m6Am) in Obesity

Proteomics raw data.

Abstract:

The prevalent m6Am mRNA cap modification was recently identified as a valid target for removal by the human obesity gene FTO along with the previously established m6A mRNA modification. However, the deposition and dynamics of m6Am in regulating obesity are unknown. Here, we investigated the liver m6A/m methylomes in mice fed on a high fat Western-diet and in ob/ob mice. We found that FTO levels were elevated in fat mice, and that genes which lost m6Am marking under obesity were overly downregulated, including the two fatty-acid-binding proteins Fabp2, and Fabp5. Furthermore, the cellular perturbation of FTO correspondingly affected protein levels of its targets. Notably, generally m6Am- but not m6A-methylated genes, were found to be highly enriched in metabolic processes. Finally, we depleted all m6A background via Mettl3 knockout, and unequivocally uncovered the association of m6Am methylation with increased mRNA stability, translation efficiency, and higher protein expression. Together, these results strongly implicate a dynamic role for m6Am in obesity-related translation regulation.