m6A RNA methylation impacts fate choices during skin morphogenesis
- Rockefeller University, United States
- The Rockefeller University, United States
- Institute for Genetics and Center for Molecular Medicine (CMMC), University of Cologne, Germany
- Weill Cornell Medical College, Cornell University, United States
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.
Data availability
The miCLIP and single-cell RNA-seq data that support the findings of this study have been deposited to the Gene Expression Omnibus (GEO) repository with the accession codes GSE147415, GSE147489 and GSE14749.
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Single-cell RNA-seq of embryonic day 17 (E17) mouse skin epithelial cells with or without Mettl3 knockoutNCBI Gene Expression Omnibus, GSE147415.
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miCLIP-seq of postnatal day 0 (P0) normal mouse skin epithelial cellsNCBI Gene Expression Omnibus, GSE147489.
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mouse skin epithelial cellsNCBI Gene Expression Omnibus, GSE147490.
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Epidermis-specific ribosome profiling to describe the translational landscape of SOX2NCBI Gene Expression Omnibus, GSE83332.
Article and author information
Author details
Funding
Damon Runyon Cancer Research Foundation (Dale F. and Betty Ann Frey Fellow,DRG-2263-16)
- Linghe Xi
National Institute of Health (R01-AR27883)
- Elaine Fuchs
National Institute of Health (R01-AR31737)
- Elaine Fuchs
National Institute of Health (R01-CA186702)
- Samie R Jaffrey
National Institute of Health (R21-CA224391)
- Samie R Jaffrey
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Valerie Horsley, Yale University, United States
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.
Version history
- Received: March 17, 2020
- Accepted: August 25, 2020
- Accepted Manuscript published: August 26, 2020 (version 1)
- Version of Record published: October 5, 2020 (version 2)
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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m6A RNA methylation impacts fate choices during skin morphogenesis
eLife 9:e56980.
https://doi.org/10.7554/eLife.56980
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