title: Transcriptional programs that control expression of the autoimmune regulator gene Aire.
abstract: Aire is a transcriptional regulator that induces promiscuous expression of thousands of genes encoding tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs that regulate its own expression have remained elusive. Here we comprehensively analyzed both cis-acting and trans-acting regulatory mechanisms and found that the Aire locus was insulated by the global chromatin organizer CTCF and was hypermethylated in cells and tissues that did not express Aire. In mTECs, however, Aire expression was facilitated by concurrent eviction of CTCF, specific demethylation of exon 2 and the proximal promoter, and the coordinated action of several transcription activators, including Irf4, Irf8, Tbx21, Tcf7 and Ctcfl, which acted on mTEC-specific accessible regions in the Aire locus.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Herzig
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shir
authors.initials: S
authors.lastname: Nevo
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Chamutal
authors.initials: C
authors.lastname: Bornstein
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Miriam R
authors.initials: MR
authors.lastname: Brezis
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Ben-Hur
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Aya
authors.initials: A
authors.lastname: Shkedy
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Eisenberg-Bord
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ben
authors.initials: B
authors.lastname: Levi
authors.affiliation: Research Group Immune Tolerance, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Delacher
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Goldfarb
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: David
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Leehee
authors.initials: L
authors.lastname: Weinberger
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Sergey
authors.initials: S
authors.lastname: Viukov
authors.affiliation: Bioinformatics Unit, Biological Services Department, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shifra
authors.identifier: 0000-0001-9604-1939
authors.initials: S
authors.lastname: Ben-Dor
authors.affiliation: Department of Infection Immunity and Inflammation, Cochin Institute, Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Giraud
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Jacob H
authors.identifier: 0000-0003-2042-9974
authors.initials: JH
authors.lastname: Hanna
authors.affiliation: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Achim
authors.identifier: 0000-0002-7928-299X
authors.initials: A
authors.lastname: Breiling
authors.affiliation: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Lyko
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
authors.affiliation: Research Group Immune Tolerance, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Feuerer
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Jakub
authors.initials: J
authors.lastname: Abramson
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001324:Autoantigens / Q000378:metabolism; D000076246:CCCTC-Binding Factor; D002454:Cell Differentiation; D002478:Cells, Cultured; D060966:Clonal Selection, Antigen-Mediated; D019175:DNA Methylation; D004847:Epithelial Cells / Q000276:immunology*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000096927:AIRE Protein; D000098815:T-bet Transcription Factor; D000099218:Interferon Regulatory Factor-4
chemical_list: D001324:Autoantigens; D000076246:CCCTC-Binding Factor; D050835:Interferon Regulatory Factors; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000096927:AIRE Protein; D000098815:T-bet Transcription Factor; D000099218:Interferon Regulatory Factor-4; C000619698:Ctcf protein, mouse