Research Article

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

Institut Cochin, INSERM U1016, France
Centre de Recherche en Transplantation et Immunologie, INSERM U1064, France
German Cancer Research Center, Germany
Harvard Medical School, United States
Institut de Biologie de l'Ecole Normale Supérieure, France
Institut Français de Bioinformatique, CNRS UMS 3601, France
Broad Institute of Harvard and MIT, United States

Apr 27, 2020

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Abstract
Data availability
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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

1. Giraud M
2. Guyon C
(2019) WT and Aire-KO mouse MEChi RNAseq profiling
NCBI Gene Expression Omnibus, GSE140683.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE140683
(2019) RNAseq profiling of Aire and Ctr-transfected HEK293 cells
NCBI Gene Expression Omnibus, GSE140738.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE140738
1. Giraud M
2. Guyon C
(2019) Stability of Aire-upregulated and Aire-neutral transcripts in medullary thymic epithelial cells
NCBI Gene Expression Omnibus, GSE140815.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE140815
1. Giraud M
2. Guyon C
3. Jmari N
(2019) Clp1 knockdown lentigenic mouse generation
NCBI Gene Expression Omnibus, GSE140878.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE140878
1. Giraud M
2. Jmari N
(2019) RNAseq profiling of Ctr and CLP1 knockdown HEK293 cells
NCBI Gene Expression Omnibus, GSE140993.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE140993
1. Giraud M
2. Jmari N
(2019) RNAseq profiling of Ctr and CLP1 knockdown HEK293 cells
NCBI Gene Expression Omnibus, GSE141118.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE141118

The following previously published data sets were used

1. Andreas R Gruber
(2012) PAR-CLIP CstF-64
NCBI Gene Expression Omnibus, GSM917676.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM917676
1. Abramson J
2. Giraud M
(2016) Aire-KO MEChi RNAseq profiling
NCBI Gene Expression Omnibus, GSE87133.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE87133
1. Abramson J
2. Giraud M
(2015) Sirt1 is essential for Aire-mediated induction of central immunological tolerance
NCBI Gene Expression Omnibus, GSE68190.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE68190

Article and author information

Author details

Clotilde Guyon

Immunology, Institut Cochin, INSERM U1016, Paris, France

Competing interests
The authors declare that no competing interests exist.
Nada Jmari

Immunology, Institut Cochin, INSERM U1016, Paris, France

Competing interests
The authors declare that no competing interests exist.
Francine Padonou

Immunology, Centre de Recherche en Transplantation et Immunologie, INSERM U1064, Nantes, France

Competing interests
The authors declare that no competing interests exist.
Yen-Chin Li

Immunology, Institut Cochin, INSERM U1016, Paris, France

Competing interests
The authors declare that no competing interests exist.
Olga Ucar

Developmental Immunology, German Cancer Research Center, Heidelberg, Germany

Competing interests
The authors declare that no competing interests exist.
Noriyuki Fujikado

Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Fanny Coulpier

Genomic platform, Institut de Biologie de l'Ecole Normale Supérieure, Paris, France

Competing interests
The authors declare that no competing interests exist.
Christophe Blanchet

IFB-Core, Institut Français de Bioinformatique, CNRS UMS 3601, Evry, France

Competing interests
The authors declare that no competing interests exist.
David E Root

Broad Institute of Harvard and MIT, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
Matthieu Giraud

Immunology, Centre de Recherche en Transplantation et Immunologie, INSERM U1064, Nantes, France

For correspondence
matthieu.giraud@inserm.fr

Competing interests
The authors declare that no competing interests exist.

"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

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.