title: Aire controls gene expression in the thymic epithelium with ordered stochasticity.
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.
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meredith
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: David
authors.initials: D
authors.lastname: Zemmour
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D000818:Animals; D019175:DNA Methylation / Q000235:genetics*; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism*; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology*; D059010:Single-Cell Analysis; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D000096927:AIRE Protein
chemical_list: D012333:RNA, Messenger; D014157:Transcription Factors; D000096927:AIRE Protein