Dynamic regulation of N6,2′-O-dimethyladenosine (m6Am) in obesity
Moshe Shay Ben-Haim, Yishay Pinto, Sharon Moshitch-Moshkovitz, Vera Hershkovitz, Nitzan Kol, Tammy Diamant-Levi, Michal Schnaider Beeri, Ninette Amariglio, Haim Cohen, Gideon Rechavi
Abstract
Abstract 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.