1. Developmental Biology
Download icon

m6A RNA methylation impacts fate choices during skin morphogenesis

  1. Linghe Xi
  2. Thomas Carroll
  3. Irina Matos
  4. Ji-Dung Luo
  5. Lisa Polak
  6. H Amalia Pasolli
  7. Jens C. Brüning
  8. Samie R Jaffrey
  9. Elaine Fuchs  Is a corresponding author
  1. Rockefeller University, United States
  2. The Rockefeller University, United States
  3. Institute for Genetics and Center for Molecular Medicine (CMMC), University of Cologne, Germany
  4. Weill Cornell Medical College, Cornell University, United States
Research Article
  • Cited 5
  • Views 2,814
  • Annotations
Cite this article as: eLife 2020;9:e56980 doi: 10.7554/eLife.56980

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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Linghe Xi

    Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  2. Thomas Carroll

    Bioinformatics Resouce Center, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  3. Irina Matos

    Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6100-8020
  4. Ji-Dung Luo

    Bioinformatics Resource Center, The Rockefeller University, New York City, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0150-1440
  5. Lisa Polak

    Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  6. H Amalia Pasolli

    Electron Microscopy Resource Center, Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  7. 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.
  8. Samie R Jaffrey

    Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3615-6958
  9. Elaine Fuchs

    Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, United States
    For correspondence
    fuchs@rockefeller.edu
    Competing interests
    Elaine Fuchs, Elaine Fuchs is a member of the Scientific Advisory Boards of L'Oreal and Arsenal Biosciences.Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1239-5316

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.

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

  1. Valerie Horsley, Yale University, United States

Publication history

  1. Received: March 17, 2020
  2. Accepted: August 25, 2020
  3. Accepted Manuscript published: August 26, 2020 (version 1)
  4. 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.

Metrics

  • 2,814
    Page views
  • 472
    Downloads
  • 5
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    2. Developmental Biology
    Shu Yang et al.
    Research Article

    Hedgehog (Hh) and bone morphogenetic proteins (BMPs) pattern the developing Drosophila wing by functioning as short- and long-range morphogens, respectively. Here, we show that a previously unknown Hh-dependent mechanism fine-tunes the activity of BMPs. Through genome-wide expression profiling of the Drosophila wing imaginal discs, we identify nord as a novel target gene of the Hh signaling pathway. Nord is related to the vertebrate Neuron Derived Neurotrophic Factor (NDNF) involved in Congenital Hypogonadotropic Hypogonadism and several types of cancer. Loss- and gain-of-function analyses implicate Nord in the regulation of wing growth and proper crossvein patterning. At the molecular level, we present biochemical evidence that Nord is a secreted BMP-binding protein and localizes to the extracellular matrix. Nord binds to Decapentaplegic (Dpp) or the heterodimer Dpp-Glass bottom boat (Gbb) to modulate their release and activity. Furthermore, we demonstrate that Nord is a dosage-depend BMP modulator, where low levels of Nord promote and high levels inhibit BMP signaling. Taken together, we propose that Hh-induced Nord expression fine tunes both the range and strength of BMP signaling in the developing Drosophila wing.

    1. Developmental Biology
    2. Evolutionary Biology
    Sarah E Westrick et al.
    Feature Article

    The Puerto Rican coquí frog Eleutherodactylus coqui (E. coqui) is both a cultural icon and a species with an unusual natural history that has attracted attention from researchers in a number of different fields within biology. Unlike most frogs, the coquí frog skips the tadpole stage, which makes it of interest to developmental biologists. The frog is best known in Puerto Rico for its notoriously loud mating call, which has allowed researchers to study aspects of social behavior such as vocal communication and courtship, while the ability of coquí to colonize new habitats has been used to explore the biology of invasive species. This article reviews research on the natural history of E. coqui and opportunities for future research.