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.
|State||Published - 10 Dec 2021|
Bibliographical noteFunding Information:
We thank the Kahn Family Foundation for their continuous support. This work was supported in part by grants from the Flight Attendant Medical Research Institute (FAMRI); the Ernest and Bonnie Beutler Research Program, by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 743168) and by the German–Israeli Project Cooperation (DIP) of the German Federal Ministry of Education and Research. GR is a member of the Sagol Neuroscience Network and holds the Djerassi Chair in Oncology at the Sackler Faculty of Medicine, Tel Aviv University. HC is a the head of the SAGOL center of healthy human aging. MSBH was supported by the Herczeg Institute of Aging. This work was performed in partial fulfillment of the requirements for a PhD degree to MSBH, Sackler School of Medicine, Tel-Aviv University. We thank Hannah Kanety for helpful comments and antibody assistance and Yshai Levin of the De Botton Protein Profiling institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science for proteomic profiling services.
© 2021, The Author(s).