The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells

Invariant natural killer T (iNKT) cells are innate-like lymphocytes that protect against infection, autoimmune disease and cancer. However, little is known about epigenetic regulation of iNKT cell development. Here, we show that the H3K27me3 histone demethylase UTX is an essential cell-intrinsic factor that controls an iNKT lineage-specific gene expression program and epigenetic landscape in a demethylase activity dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT signature genes due to a decrease in activation-associated H3K4me3 and an increase in repressive H3K27me3 marks within the promoters that UTX occupies. We identified JunB as a novel regulator of iNKT development and show that target gene expression of both JunB and iNKT master transcription factor PLZF was UTX-dependent. We determined iNKT super-enhancers and demonstrated that UTX-mediated regulation of super-enhancer accessibility was a key mechanism for iNKT lineage commitment. These findings reveal how UTX regulates iNKT cell development through multiple epigenetic mechanisms.