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

Natural killer T cells in the thymus are CD1d-restricted cells that are selected at the CD4 + CD8 + double-positive stage and require a variety of transcription factors for their development. Orkin, Winau and colleagues show that the histone demethylase UTX serves an essential role in the transcriptional control of the thymic maturation of these cells through multiple epigenetic mechanisms. Invariant natural killer T cells ( i NKT cells) are innate-like lymphocytes that protect against infection, autoimmune disease and cancer. However, little is known about the epigenetic regulation of i NKT cell development. Here we found that the H3K27me3 histone demethylase UTX was an essential cell-intrinsic factor that controlled an i NKT-cell lineage-specific gene-expression program and epigenetic landscape in a demethylase-activity-dependent manner. UTX-deficient i NKT cells exhibited impaired expression of i NKT cell signature genes due to a decrease in activation-associated H3K4me3 marks and an increase in repressive H3K27me3 marks within the promoters occupied by UTX. We found that JunB regulated i NKT cell development and that the expression of genes that were targets of both JunB and the i NKT cell master transcription factor PLZF was UTX dependent. We identified i NKT cell super-enhancers and demonstrated that UTX-mediated regulation of super-enhancer accessibility was a key mechanism for commitment to the i NKT cell lineage. Our findings reveal how UTX regulates the development of i NKT cells through multiple epigenetic mechanisms.