Aire controls gene expression in the thymic epithelium with ordered stochasticity.

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  • Additional Information
    • Source:
      Publisher: Nature America Inc Country of Publication: United States NLM ID: 100941354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1529-2916 (Electronic) Linking ISSN: 15292908 NLM ISO Abbreviation: Nat Immunol Subsets: MEDLINE
    • Publication Information:
      Original Publication: New York, NY : Nature America Inc. c2000-
    • Subject Terms:
      DNA Methylation/*genetics ; Epithelial Cells/*immunology ; Gene Expression Regulation/*immunology ; RNA, Messenger/*metabolism ; Self Tolerance/*immunology ; Thymus Gland/*immunology ; Transcription Factors/*immunology; Animals ; Epithelial Cells/metabolism ; Mice ; Self Tolerance/genetics ; Single-Cell Analysis ; Thymus Gland/cytology ; Thymus Gland/metabolism ; Transcription Factors/genetics ; AIRE Protein
    • 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.
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    • Grant Information:
      R01 DK060027 United States DK NIDDK NIH HHS; R37 DK060027 United States DK NIDDK NIH HHS; DK060027 United States DK NIDDK NIH HHS
    • Accession Number:
      0 (RNA, Messenger)
      0 (Transcription Factors)
    • Publication Date:
      Date Created: 20150804 Date Completed: 20151109 Latest Revision: 20240610
    • Publication Date:
      20240610
    • Accession Number:
      PMC4632529
    • Accession Number:
      10.1038/ni.3247
    • Accession Number:
      26237550