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 Y. Cohen, Gideon Rechavi

Research output: Contribution to journalArticlepeer-review

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 investigate the liver m6A/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 m6Am 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 m6Am- but not m6A-methylated genes, are found to be highly enriched in metabolic processes. Finally, we deplete all m6A background via Mettl3 knockout, and unequivocally uncover 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.

Original languageEnglish
Article number7185
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

Fingerprint

Dive into the research topics of 'Dynamic regulation of N6,2′-O-dimethyladenosine (m6Am) in obesity'. Together they form a unique fingerprint.

Cite this