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Genome Res. 2014 Dec;24(12):1918-31. doi: 10.1101/gr.171645.113. Epub 2014 Sep 15.

Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia.

Author information

1
MRC Computational Genomics Analysis and Training Programme, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, United Kingdom; stephen.sansom@kennedy.ox.ac.uk stephen.sansom@cantab.net Georg.Hollander@paediatrics.ox.ac.uk Georg-A.Hollaender@unibas.ch.
2
Paediatric Immunology, Department of Biomedicine, University of Basel, and The Basel University Children's Hospital, Basel, 4058, Switzerland;
3
Wellcome Trust Sanger Institute-EBI Single Cell Genomics Centre, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom;
4
Developmental Immunology, Department of Paediatrics, and the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom.
5
MRC Computational Genomics Analysis and Training Programme, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, United Kingdom;
6
MRC Computational Genomics Analysis and Training Programme, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, United Kingdom; Wellcome Trust Sanger Institute-EBI Single Cell Genomics Centre, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom;
7
Paediatric Immunology, Department of Biomedicine, University of Basel, and The Basel University Children's Hospital, Basel, 4058, Switzerland; Developmental Immunology, Department of Paediatrics, and the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom.

Abstract

Promiscuous gene expression (PGE) by thymic epithelial cells (TEC) is essential for generating a diverse T cell antigen receptor repertoire tolerant to self-antigens, and thus for avoiding autoimmunity. Nevertheless, the extent and nature of this unusual expression program within TEC populations and single cells are unknown. Using deep transcriptome sequencing of carefully identified mouse TEC subpopulations, we discovered a program of PGE that is common between medullary (m) and cortical TEC, further elaborated in mTEC, and completed in mature mTEC expressing the autoimmune regulator gene (Aire). TEC populations are capable of expressing up to 19,293 protein-coding genes, the highest number of genes known to be expressed in any cell type. Remarkably, in mouse mTEC, Aire expression alone positively regulates 3980 tissue-restricted genes. Notably, the tissue specificities of these genes include known targets of autoimmunity in human AIRE deficiency. Led by the observation that genes induced by Aire expression are generally characterized by a repressive chromatin state in somatic tissues, we found these genes to be strongly associated with H3K27me3 marks in mTEC. Our findings are consistent with AIRE targeting and inducing the promiscuous expression of genes previously epigenetically silenced by Polycomb group proteins. Comparison of the transcriptomes of 174 single mTEC indicates that genes induced by Aire expression are transcribed stochastically at low cell frequency. Furthermore, when present, Aire expression-dependent transcript levels were 16-fold higher, on average, in individual TEC than in the mTEC population.

PMID:
25224068
PMCID:
PMC4248310
DOI:
10.1101/gr.171645.113
[Indexed for MEDLINE]
Free PMC Article

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