Aire controls gene expression in the thymic epithelium with ordered stochasticity

Matthew Meredith; David Zemmour; Diane Mathis; Christophe Benoist

doi:10.1038/ni.3247

Aire controls gene expression in the thymic epithelium with ordered stochasticity

Matthew Meredith, David Zemmour, Diane Mathis, Christophe Benoist

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

123 Scopus citations

Abstract

The transcription factor Aire controls immunological tolerance by inducing the ectopic thymic expression of many tissue-specific genes, acting broadly by removing stops on the transcriptional machinery. To better understand Aire's specificity, we performed single-cell RNA-seq and DNA-methylation analysis of Aire-sufficient and Aire-deficient medullary epithelial cells (mTECs). Each of Aire's target genes was induced in only a minority of mTECs, independently of DNA-methylation patterns, as small inter-chromosomal gene clusters activated in concert in a proportion of mTECs. These microclusters differed between individual mice. Thus, our results suggest an organization of the DNA or of the epigenome that results from stochastic determinism but is 'bookmarked' and stable through mTEC divisions, which ensures more effective presentation of self antigens and favors diversity of self-tolerance between individuals.

Original language	English (US)
Pages (from-to)	942-949
Number of pages	8
Journal	Nature Immunology
Volume	16
Issue number	9
DOIs	https://doi.org/10.1038/ni.3247
State	Published - Aug 19 2015

Bibliographical note

Funding Information:
We thank S. Mostafavi for advice on computational analysis; M. Anderson (University of California, San Francisco) for the Aire-GFP line; and K. Hattori, G. Buruzula, and K. Waraska for help with mice, sorting and sequencing. Supported by the US National Institutes of Health (DK060027; and a Children’s Hospital in Pediatric Gastroenterology training grant for M.M.) and Boehringer Ingelheim Fonds (D.Z.).

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© 2015 Nature America, Inc.

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Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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abstract = "The transcription factor Aire controls immunological tolerance by inducing the ectopic thymic expression of many tissue-specific genes, acting broadly by removing stops on the transcriptional machinery. To better understand Aire's specificity, we performed single-cell RNA-seq and DNA-methylation analysis of Aire-sufficient and Aire-deficient medullary epithelial cells (mTECs). Each of Aire's target genes was induced in only a minority of mTECs, independently of DNA-methylation patterns, as small inter-chromosomal gene clusters activated in concert in a proportion of mTECs. These microclusters differed between individual mice. Thus, our results suggest an organization of the DNA or of the epigenome that results from stochastic determinism but is 'bookmarked' and stable through mTEC divisions, which ensures more effective presentation of self antigens and favors diversity of self-tolerance between individuals.",

author = "Matthew Meredith and David Zemmour and Diane Mathis and Christophe Benoist",

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Aire controls gene expression in the thymic epithelium with ordered stochasticity

Abstract

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