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An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus


Promiscuous expression of tissue-restricted auto-antigens in the thymus imposes T-cell tolerance and provides protection from autoimmune diseases1,2,3. Promiscuous expression of a set of self-antigens occurs in medullary thymic epithelial cells4,5 and is partly controlled by the autoimmune regulator (AIRE), a nuclear protein for which loss-of-function mutations cause the type 1 autoimmune polyendocrine syndrome6,7. However, additional factors must be involved in the regulation of this promiscuous expression. Here we describe a mechanism controlling thymic transcription of a prototypic tissue-restricted human auto-antigen gene, CHRNA1. This gene encodes the α-subunit of the muscle acetylcholine receptor, which is the main target of pathogenic auto-antibodies in autoimmune myasthenia gravis8,9. On re-sequencing the CHRNA1 gene, we identified a functional bi-allelic variant in the promoter that is associated with early onset of disease in two independent human populations (France and United Kingdom). We show that this variant prevents binding of interferon regulatory factor 8 (IRF8) and abrogates CHRNA1 promoter activity in thymic epithelial cells in vitro. Notably, both the CHRNA1 promoter variant and AIRE modulate CHRNA1 messenger RNA levels in human medullary thymic epithelial cells ex vivo and also in a transactivation assay. These findings reveal a critical function of AIRE and the interferon signalling pathway in regulating quantitative expression of this auto-antigen in the thymus, suggesting that together they set the threshold for self-tolerance versus autoimmunity.

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Figure 1: rs16862847 allele variation affects IRF8 binding.
Figure 2: Characterization of IRF8-dependent CHRNA1 transcriptional activity in the TEC line.
Figure 3: Effect of rs16862847 and AIRE on CHRNA1 expression levels in mTECs.


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This study was funded by INSERM (Institut National de la Santé et de la Recherche Médicale) and the Association Française contre les Myopathies. M.G. was supported by a fellowship of the Fondation pour la Recherche Médicale in Oxford and of the European Molecular Biology Organization in Trieste. R.T. and B.K. have been supported by the DKFZ, the Sonderforschungsbereich 405 and EU-Thymaide; F.E.B. and F.P. by the Associazione Italiana Ricerca Cancro. D.B., N.W. and A.V. thank the UK MRC, Muscular Dystrophy Campaign and the Myasthenia Gravis Association for support. We thank the participating patients. We thank J. Newsom-Davis for clinical samples and expertise; S. Krumeich and G. Picarda for technical assistance; W. Savino for providing us with an aliquot of the TEC line; A. Harris for advice on EMSA; M. Lathrop for advice on genetic data analysis; P. Peterson for the gift of the AIRE expression plasmid; S. Hagl and members of the Department of Cardiac Surgery for providing human thymic tissue; K. Hexel and M. Scheuermann for cell sorting; G. Moldenhauer for providing monoclonal antibodies; and A. Kopp-Schneider for statistical analysis.

Author Contributions M.G. did the genomic experiments, EMSAs, made the reporter constructs, carried out transfections, RNAi and ChIP, analysed the data, and wrote the manuscript; R.T. carried out the experiments related to thymic gene expression; C.V. did genotyping and edited the manuscript; X.K. analysed the genetic data and edited the manuscript; M.L.-S. provided expertise to M.G. on gene cloning and proofread the manuscript; F.P. and F.E.B. provided expertise on RNA splicing analysis to M.G., when he was in Trieste, and proofread the manuscript; B.E., C.T. and P.G. recruited the French patients; A.V. and N.W. helped plan the project, provided access to the UK cohort and edited the manuscript; D.B. helped devise the experiments related to EMSAs and luciferase reporter constructs, supervised M.G. when he was in Oxford, and edited the manuscript; B.K. devised and supervised experiments related to promiscuous gene expression and wrote the manuscript; H.-J.G. coordinated the project, analysed the data and wrote the manuscript.

Newly identified SNPs (listed with an asterisk in Supplementary Table 1; accession numbers also listed) have been deposited in dbSNP.

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Correspondence to Henri-Jean Garchon.

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This file contains Supplementary Tables 1-4 and Supplementary Figures 1-8 with Legends, Supplementary Discussion and additional references. (PDF 2885 kb)

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Giraud, M., Taubert, R., Vandiedonck, C. et al. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448, 934–937 (2007).

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