2. Academic Validation
  3. Dynamic regulation of N6,2'-O-dimethyladenosine (m6Am) in obesity

Dynamic regulation of N6,2'-O-dimethyladenosine (m6Am) in obesity

  • Nat Commun. 2021 Dec 10;12(1):7185. doi: 10.1038/s41467-021-27421-2.
Moshe Shay Ben-Haim  # 1 2 3 4,  Yishay Pinto  # 5,  Sharon Moshitch-Moshkovitz 1 2 3,  Vera Hershkovitz 1 3,  Nitzan Kol 1 3,  Tammy Diamant-Levi 1 3,  Michal Schnaider Beeri 6 7,  Ninette Amariglio 1 3 5,  Haim Y Cohen 8,  Gideon Rechavi 9 10 11
Affiliations

Affiliations

  • 1 Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel.
  • 2 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 3 The Wohl Institute for Translational Medicine, Chaim Sheba Medical Center, Tel Hashomer, Israel.
  • 4 Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel.
  • 5 The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
  • 6 The Joseph Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel Hashomer, Israel.
  • 7 Mount Sinai School of Medicine, New York, NY, USA.
  • 8 The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel. Haim.Cohen@biu.ac.il.
  • 9 Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel. Gidi.Rechavi@sheba.health.gov.il.
  • 10 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Gidi.Rechavi@sheba.health.gov.il.
  • 11 The Wohl Institute for Translational Medicine, Chaim Sheba Medical Center, Tel Hashomer, Israel. Gidi.Rechavi@sheba.health.gov.il.
  • # Contributed equally.
PMID: 34893620 DOI: 10.1038/s41467-021-27421-2
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.

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