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 () and Gideon Rechavi ()
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Moshe Shay Ben-Haim: Cancer Research Center, Chaim Sheba Medical Center
Yishay Pinto: Bar-Ilan University
Sharon Moshitch-Moshkovitz: Cancer Research Center, Chaim Sheba Medical Center
Vera Hershkovitz: Cancer Research Center, Chaim Sheba Medical Center
Nitzan Kol: Cancer Research Center, Chaim Sheba Medical Center
Tammy Diamant-Levi: Cancer Research Center, Chaim Sheba Medical Center
Michal Schnaider Beeri: The Joseph Sagol Neuroscience Center, Chaim Sheba Medical Center
Ninette Amariglio: Cancer Research Center, Chaim Sheba Medical Center
Haim Y. Cohen: Bar-Ilan University
Gideon Rechavi: Cancer Research Center, Chaim Sheba Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27421-2

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DOI: 10.1038/s41467-021-27421-2

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