1. Genetics and Genomics
  2. Immunology and Inflammation

Aire-dependent genes undergo Clp1-mediated 3'UTR shortening associated with higher transcript stability in the thymus

  1. Clotilde Guyon
  2. Nada Jmari
  3. Francine Padonou
  4. Yen-Chin Li
  5. Olga Ucar
  6. Noriyuki Fujikado
  7. Fanny Coulpier
  8. Christophe Blanchet
  9. David E Root
  10. Matthieu Giraud  Is a corresponding author
  1. Institut Cochin, INSERM U1016, France
  2. Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, France
  3. German Cancer Research Center, Germany
  4. Harvard Medical School, United States
  5. Institut de Biologie de l'Ecole Normale Supérieure, France
  6. Institut Français de Bioinformatique, CNRS UMS 3601, France
  7. Broad Institute of Harvard and MIT, United States
https://doi.org/10.7554/eLife.52985
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  1. Clotilde Guyon
  2. Nada Jmari
  3. Francine Padonou
  4. Yen-Chin Li
  5. Olga Ucar
  6. Noriyuki Fujikado
  7. Fanny Coulpier
  8. Christophe Blanchet
  9. David E Root
  10. Matthieu Giraud
(2020)
Aire-dependent genes undergo Clp1-mediated 3'UTR shortening associated with higher transcript stability in the thymus
eLife 9:e52985.
https://doi.org/10.7554/eLife.52985
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Abstract

The ability of the immune system to avoid autoimmune disease relies on tolerization of thymocytes to self-antigens whose expression and presentation by thymic medullary epithelial cells (mTECs) is controlled predominantly by Aire at the transcriptional level and possibly regulated at other unrecognized levels. Aire-sensitive gene expression is influenced by several molecular factors, some of which belong to the 3'end processing complex, suggesting they might impact transcript stability and levels through an effect on 3'UTR shortening. We discovered that Aire-sensitive genes display a pronounced preference for short-3'UTR transcript isoforms in mTECs, a feature preceding Aire's expression and correlated with the preferential selection of proximal polyA sites by the 3'end processing complex. Through an RNAi screen and generation of a lentigenic mouse, we found that one factor, Clp1, promotes 3'UTR shortening associated with higher transcript stability and expression of Aire-sensitive genes, revealing a post-transcriptional level of control of Aire-activated expression in mTECs.

Data availability

All RNAseq and microarray data are deposited in the NCBI Gene Expression Omnibus database (GEO).

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

Article and author information

Author details

  1. Clotilde Guyon

    Immunology, Institut Cochin, INSERM U1016, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  2. Nada Jmari

    Immunology, Institut Cochin, INSERM U1016, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  3. Francine Padonou

    Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France
    Competing interests
    The authors declare that no competing interests exist.

  4. Yen-Chin Li

    Immunology, Institut Cochin, INSERM U1016, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  5. Olga Ucar

    Developmental Immunology, German Cancer Research Center, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.

  6. Noriyuki Fujikado

    Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Fanny Coulpier

    Genomic platform, Institut de Biologie de l'Ecole Normale Supérieure, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  8. Christophe Blanchet

    IFB-Core, Institut Français de Bioinformatique, CNRS UMS 3601, Evry, France
    Competing interests
    The authors declare that no competing interests exist.

  9. David E Root

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Matthieu Giraud

    Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France
    For correspondence
    matthieu.giraud@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1208-9677

Funding

Agence Nationale de la Recherche (Research grant,2011-CHEX-001-R12004KK)

  • Matthieu Giraud

European Commission (Career Integration Grant,CIG PCIG9-GA-2011-294212)

  • Matthieu Giraud

Agence Nationale de la Recherche (Investissements d'Avenir,ANR-10-INBS-09)

  • Fanny Coulpier

Agence Nationale de la Recherche (Investissements d'Avenir,ANR-11-INBS-0013)

  • Christophe Blanchet

Fondation pour la Recherche Médicale (Graduate Student Fellowship,FDT20150532551)

  • Clotilde Guyon

Fondation pour la Recherche Médicale (Bioinformatics engineer grant)

  • Yen-Chin Li

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Mice were housed, bred and manipulated in specific-pathogen-free conditions at Cochin Institute according to the guidelines of the French Veterinary Department and under procedures approved by the Paris-Descartes Ethical Committee for Animal Experimentation (decision CEEA34.MG.021.11 or APAFIS #3683 No 2015062411489297 for lentigenic mouse generation)

Copyright

© 2020, Guyon 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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