title: Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus.
abstract: The thymus has spatially distinct microenvironments, the cortex and the medulla, where the developing T-cells are selected to mature or die through the interaction with thymic stromal cells. To establish the immunological self in the thymus, medullary thymic epithelial cells (mTECs) express diverse sets of tissue-specific self-antigens (TSAs). This ectopic expression of TSAs largely depends on the transcriptional regulator Aire, yet the mechanism controlling Aire expression itself remains unknown. Here, we show that Jmjd6, a dioxygenase that catalyses lysyl hydroxylation of splicing regulatory proteins, is critical for Aire expression. Although Jmjd6 deficiency does not affect abundance of Aire transcript, the intron 2 of Aire gene is not effectively spliced out in the absence of Jmjd6, resulting in marked reduction of mature Aire protein in mTECs and spontaneous development of multi-organ autoimmunity in mice. These results highlight the importance of intronic regulation in controlling Aire protein expression.
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Yanagihara
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Research Centre for Advanced Immunology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sanematsu
authors.affiliation: Division of Bioinformatics, Multi-scale Research Centre for Medical Science, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Sato
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Research Centre for Advanced Immunology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Uruno
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Research Centre for Advanced Immunology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Xuefeng
authors.identifier: http://orcid.org/0000-0002-5281-1425
authors.initials: X
authors.lastname: Duan
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tomino
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Harada
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Mayuki
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Research Centre for Advanced Immunology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Section of Infection Biology, Department of Functional Bioscience, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0175, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: Division of Bioinformatics, Multi-scale Research Centre for Medical Science, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Mikita
authors.initials: M
authors.lastname: Suyama
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Research Centre for Advanced Immunology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Fukui
authors.initials: F
authors.lastname: Yoshinori
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology; D015139:Blotting, Southern; D004847:Epithelial Cells; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007438:Introns / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009924:Organ Culture Techniques; D012326:RNA Splicing / Q000235:genetics* / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017634:Self Tolerance / Q000235:genetics* / Q000276:immunology; D017423:Sequence Analysis, RNA; D013950:Thymus Gland / Q000276:immunology* / Q000637:transplantation; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology; D000096927:AIRE Protein
chemical_list: D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000096927:AIRE Protein; C498708:Ptdsr protein, mouse