title: A highly conserved NF-κB-responsive enhancer is critical for thymic expression of Aire in mice.
abstract: Autoimmune regulator (Aire) has a unique expression pattern in thymic medullary epithelial cells (mTECs), in which it plays a critical role in the activation of tissue-specific antigens. The expression of Aire in mTECs is activated by receptor activator of nuclear factor κB (RANK) signaling; however, the molecular mechanism behind this activation is unknown. Here, we characterize a conserved noncoding sequence 1 (CNS1) containing two NF-κB binding sites upstream of the Aire coding region. We show that CNS1-deficient mice lack thymic expression of Aire and share several features of Aire-knockout mice, including downregulation of Aire-dependent genes, impaired terminal differentiation of the mTEC population, and reduced production of thymic Treg cells. In addition, we show that CNS1 is indispensable for RANK-induced Aire expression and that CNS1 is activated by NF-κB pathway complexes containing RelA. Together, our results indicate that CNS1 is a critical link between RANK signaling, NF-κB activation, and thymic expression of Aire.
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Uku
authors.initials: U
authors.lastname: Haljasorg
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Bichele
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Mario
authors.initials: M
authors.lastname: Saare
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Mithu
authors.initials: M
authors.lastname: Guha
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Julia
authors.initials: J
authors.lastname: Maslovskaja
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Karin
authors.initials: K
authors.lastname: Kõnd
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Anu
authors.initials: A
authors.lastname: Remm
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Maire
authors.initials: M
authors.lastname: Pihlap
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Laura
authors.initials: L
authors.lastname: Tomson
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Kai
authors.initials: K
authors.lastname: Kisand
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Martti
authors.initials: M
authors.lastname: Laan
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
mesh_terms: D000818:Animals; D001665:Binding Sites; D004847:Epithelial Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000502:physiology; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000096927:AIRE Protein
chemical_list: D016328:NF-kappa B; D053246:Receptor Activator of Nuclear Factor-kappa B; D014157:Transcription Factors; D000096927:AIRE Protein; C505687:Tnfrsf11a protein, mouse
keywords: Autoimmune regulator · Enhancer · NF-κB · Receptor activator of nuclear factor κB · Thymic medulla