m6A RNA methylation impacts fate choices during skin morphogenesis
Abstract
N6-methyladenosine is the most prominent RNA modification in mammals. Here we study mouse skin embryogenesis to tackle m6A’s functions and physiological importance. We first landscape the m6A modifications on skin epithelial progenitor mRNAs. Contrasting with in vivo ribosomal profiling, we unearth a correlation between m6A-modification in coding sequences and enhanced translation, particularly of key morphogenetic signaling pathways. Tapping physiological relevance, we show that m6A loss profoundly alters these cues and perturbs cellular fate choices and tissue architecture in all skin lineages. By single-cell transcriptomics and bioinformatics, both signaling and canonical translation pathways show significant downregulation after m6A loss. Interestingly, however, many highly m6A-modified mRNAs are markedly upregulated upon m6A loss, and they encode RNA-methylation, RNA-processing and RNA-metabolism factors. Together, our findings suggest that m6A functions to enhance translation of key morphogenetic regulators, while also destabilizing sentinel mRNAs that are primed to activate rescue pathways when m6A levels drop.
Article and author information
Author details
Linghe Xi
Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, United States
Competing interests
No competing interests declared.
Thomas Carroll
Bioinformatics Resouce Center, The Rockefeller University, New York, United States
Competing interests
No competing interests declared.
Lisa Polak
Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, United States
Competing interests
No competing interests declared.
H Amalia Pasolli
Electron Microscopy Resource Center, Rockefeller University, New York, United States
Competing interests
No competing interests declared.
Jens C. Brüning
Department of Mouse Genetics and Metabolism, Institute for Genetics and Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
Competing interests
No competing interests declared.
Funding
Damon Runyon Cancer Research Foundation (Dale F. and Betty Ann Frey Fellow,DRG-2263-16)
National Institute of Health (R01-AR27883)
National Institute of Health (R01-AR31737)
National Institute of Health (R01-CA186702)
National Institute of Health (R21-CA224391)
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experimentation: All mouse strains were housed in an AAALAC-accredited facility and experiments were conducted according to the Rockefeller University’s Institutional Animal Care and Use Committee (IACUC), and NIH guidelines for Animal Care and Use. All animal procedures used in this study are described in our #20012-H & #17091-H protocols, which had been previously reviewed and approved by the Rockefeller University IACUC.
Reviewing Editor
Valerie Horsley, Yale University, United States
Publication history
Received: March 17, 2020
Accepted: August 25, 2020
Accepted Manuscript published: August 26, 2020 (version 1)
Copyright
© 2020, Xi et al.This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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