Abstract
Abstract iNKT cells are innate-like lymphocytes that protect against infection, autoimmune disease, and cancer. However, the role of epigenetic regulation in iNKT cell biology remains elusive. Here, we show that the H3K27me3 histone demethylase UTX is an essential cell-intrinsic factor for iNKT cell development in the thymus. UTX-deficient iNKT cells exhibit impaired expression of iNKT signature genes, including NK cell receptors and the transcription factor Tbx21. Epigenetic profiling uncovers a decrease in activation-associated H3K4me3 and an increase in repressive H3K27me3 marks within the promoters of downregulated signature genes. UTX binds to these promoters and its enzymatic demethylase activity is important for establishing the iNKT gene expression program. Moreover, we identify the AP-1 transcription factor JunB as novel master regulator of the iNKT cell gene signature, highlighted by its molecular interaction with UTX. Finally, iNKT cells harbor super-enhancers for their key factors T-bet, PLZF, and JunB, underlining their role in lineage specification.
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