Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus

Toyoshi Yanagihara, Fumiyuki Sanematsu, Tetsuya Sato, Takehito Uruno, Xuefeng Duan, Takahiro Tomino, Yosuke Harada, Mayuki Watanabe, Yuqing Wang, Yoshihiko Tanaka, Yoichi Nakanishi, Mikita Suyama and Fukui Yoshinori ()
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Toyoshi Yanagihara: Medical Institute of Bioregulation, Kyushu University
Fumiyuki Sanematsu: Medical Institute of Bioregulation, Kyushu University
Tetsuya Sato: Multi-scale Research Centre for Medical Science, Medical Institute of Bioregulation, Kyushu University
Takehito Uruno: Medical Institute of Bioregulation, Kyushu University
Xuefeng Duan: Medical Institute of Bioregulation, Kyushu University
Takahiro Tomino: Medical Institute of Bioregulation, Kyushu University
Yosuke Harada: Medical Institute of Bioregulation, Kyushu University
Mayuki Watanabe: Medical Institute of Bioregulation, Kyushu University
Yuqing Wang: Research Centre for Advanced Immunology, Kyushu University
Yoshihiko Tanaka: Section of Infection Biology, Fukuoka Dental College
Yoichi Nakanishi: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University
Mikita Suyama: Multi-scale Research Centre for Medical Science, Medical Institute of Bioregulation, Kyushu University
Fukui Yoshinori: Medical Institute of Bioregulation, Kyushu University

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9820

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