An evolutionarily conserved mutual interdependence between Aire and microRNAs in promiscuous gene expression

Authors

  • Olga Ucar,

    1. Division of Developmental Immunology, German Cancer Research Center, Heidelberg, Germany
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  • Lars-Oliver Tykocinski,

    1. Division of Developmental Immunology, German Cancer Research Center, Heidelberg, Germany
    Current affiliation:
    1. Department of Internal Medicine V, Division of Rheumatology, University of Heidelberg, Heidelberg, Germany
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  • James Dooley,

    1. Autoimmune Genetics Laboratory, VIB, Leuven, Belgium
    2. Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium
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  • Adrian Liston,

    1. Autoimmune Genetics Laboratory, VIB, Leuven, Belgium
    2. Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium
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  • Bruno Kyewski

    Corresponding author
    • Division of Developmental Immunology, German Cancer Research Center, Heidelberg, Germany
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Full correspondence: Dr. Bruno Kyewski, Division of Developmental Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany

Fax: +49-6221-423737

e-mail: b.kyewski@dkfz.de

Abstract

The establishment and maintenance of central tolerance depends to a large extent on the ability of medullary thymic epithelial cells to express a variety of tissue-restricted antigens, the so-called promiscuous gene expression (pGE). Autoimmune regulator (Aire) is to date the best characterised transcriptional regulator known to at least partially coordinate pGE. There is accruing evidence that the expression of Aire-dependent and -independent genes is modulated by higher order chromatin configuration, epigenetic modifications and post-transcriptional control. Given the involvement of microRNAs (miRNAs) as potent post-transcriptional modulators of gene expression, we investigated their role in the regulation of pGE in purified mouse and human thymic epithelial cells (TECs). Microarray profiling of TEC subpopulations revealed evolutionarily conserved cell type and differentiation-specific miRNA signatures with a subset of miRNAs being significantly upregulated during terminal medullary thymic epithelial cell differentiation. The differential regulation of this subset of miRNAs was correlated with Aire expression and some of these miRNAs were misexpressed in the Aire knockout thymus. In turn, the specific absence of miRNAs in TECs resulted in a progressive reduction of Aire expression and pGE, affecting both Aire-dependent and -independent genes. In contrast, the absence of miR-29a only affected the Aire-dependent gene pool. These findings reveal a mutual interdependence of miRNA and Aire.

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