RRC ID 36523
Author Yanagihara T, Sanematsu F, Sato T, Uruno T, Duan X, Tomino T, Harada Y, Watanabe M, Wang Y, Tanaka Y, Nakanishi Y, Suyama M, Yoshinori F.
Title Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus.
Journal Nat Commun
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.
Volume 6
Pages 8820
Published 2015-11-4
DOI 10.1038/ncomms9820
PII ncomms9820
PMID 26531897
PMC PMC4667615
MeSH Animals Autoimmunity / genetics* Autoimmunity / immunology Blotting, Southern Epithelial Cells Flow Cytometry Fluorescent Antibody Technique Gene Expression Regulation* HEK293 Cells Humans Immunoblotting Introns / genetics Mice Mice, Knockout Mice, Nude Organ Culture Techniques RNA Splicing / genetics* RNA Splicing / immunology Real-Time Polymerase Chain Reaction Receptors, Cell Surface / genetics* Receptors, Cell Surface / immunology Reverse Transcriptase Polymerase Chain Reaction Self Tolerance / genetics* Self Tolerance / immunology Sequence Analysis, RNA Thymus Gland / immunology* Thymus Gland / transplantation Transcription Factors / genetics* Transcription Factors / immunology
IF 12.121
Times Cited 16
Mice RBRC03120