title: Identification of a novel cis-regulatory element essential for immune tolerance.
abstract: Thymic central tolerance is essential to preventing autoimmunity. In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by driving the expression of a diverse set of tissue-specific antigens (TSAs), which are presented and help tolerize self-reactive thymocytes. Interestingly, Aire has a highly tissue-restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectable levels in adults. Despite this high level of tissue specificity, the cis-regulatory elements that control Aire expression have remained obscure. Here, we identify a highly conserved noncoding DNA element that is essential for Aire expression. This element shows enrichment of enhancer-associated histone marks in mTECs and also has characteristics of being an NF-κB-responsive element. Finally, we find that this element is essential for Aire expression in vivo and necessary to prevent spontaneous autoimmunity, reflecting the importance of this regulatory DNA element in promoting immune tolerance.
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Taylor N
authors.initials: TN
authors.lastname: LaFlam
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Grégory
authors.initials: G
authors.lastname: Seumois
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Corey N
authors.initials: CN
authors.lastname: Miller
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Wint
authors.initials: W
authors.lastname: Lwin
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Kayla J
authors.initials: KJ
authors.lastname: Fasano
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Michael
authors.initials: M
authors.lastname: Waterfield
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Irina
authors.initials: I
authors.lastname: Proekt
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Pandurangan
authors.initials: P
authors.lastname: Vijayanand
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143 manderson@diabetes.ucsf.edu.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics / Q000276:immunology; D000096927:AIRE Protein
chemical_list: D004247:DNA; D016328:NF-kappa B; D014157:Transcription Factors; D000096927:AIRE Protein