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

Abstract

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.

In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis

“…UTX is the major demethylase of H3K27me3 (15), and a previous study has shown that loss of UTX results in deregulation of the cell cycle via RB-dependent pathways (36). Moreover, UTX has been reported to regulate the development of invariant natural killer T cells via the epigenetic program (37). Interestingly, UTX somatic mutations are frequently detected in various epithelial cancers, including multiple myeloma, esophageal squamous cell carcinoma, and lung cancer (38).…”

Transcription factor-dependent ‘anti-repressive’ mammalian enhancers exclude H3K27me3 from extended genomic domains

“…Cis elements recruit the H3K27 demethylase KDM6A/ UTX Our findings collectively suggest that type 1A domains are intrinsically predisposed to acquiring H3K27me3, with deposition and erasure occurring dynamically. One possible way for enhancers to offset H3K27me3 spread is to recruit a demethylase such as KDM6A/UTX, which limits H3K27me3 accumulation at promoters (Agger et al 2007;Arcipowski et al 2016) and is reported to bind certain heart-specific and T-cell-specific enhancers (Lee et al 2012;Beyaz et al 2017). To test whether intestinal CDX2-dependent enhancers recruit KDM6A to avoid H3K27me3 accumulation, we first confirmed that the KDM6A antibody recognizes a single protein of the expected mass by immunoblotting ( Supplemental Fig.…”

Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells

“…The pharmacological inhibition of BRD4 by JQ1 inhibited a broad range of TNF-α-responsive genes, suggesting the important role of SEs in the inflammatory response of ECs (Brown et al, 2014). More recently, Beyaz et al showed that UTX facilitates the accessibility of SEs that establish the cell identity of invariant natural killer T cells, in accordance with low levels of H3K27me3 (Beyaz et al, 2017). This study raised the possibility that the erasure of repressive histone marks by histone demethylases correlates with the formation of SEs and the activation of associated genes; however, these points have not been addressed during the early inflammatory responses.…”