Hypoxia-sensing by Colitogenic CD4+ T cells Is Regulated by the Histone Demethylase UTX [H3K27me3 CUT&Tag]
Hypoxia exacerbates tissue damage in inflammatory bowel disease (IBD). To counteract the deleterious effects of oxygen deprivation, cells within hypoxic tissues activate multiple adaptive mechanisms. Much attention has focused on adaptive pathways regulated by HIF (hypoxia inducible factor) transcription factors, and pharmacologic HIF stabilization is a promising therapeutic approach for IBD. However, recent evidence suggests that hypoxia-induction of cellular transcriptional programs can be mediated not only by HIF transcription factors, but also by oxygen-sensing epigenetic regulator, UTX. Here, we identify a key role for an UTX in modulating colitis severity. Unlike HIF-mediated pathways that act on gut epithelial cells, UTX-mediated pathways function in a T cell-intrinsic manner to protect against colitis. Hypoxia impairs the histone demethylase activity of UTX, which leads to accumulation of repressive H3K27me3 marks at IL12/STAT4 pathway genes (Il12rb2, Tbx21, and Ifng), decreased CD4+ T cell IFN-? production, and increased CD4+ regulatory T cells (Tregs). Moreover, T cell specific UTX deletion protects mice from autoimmune colitis, which demonstrates that deactivation of UTX restores immune regulation in hypoxia-associated inflammation.  Together these findings suggest that modulating UTX's histone demethylase activity in T cells may be a new pharmacologic target for harnessing hypoxia-induced adaptive pathways in colitis. Overall design: To identify changes in H3K27me3 levels at gene loci  in response to loss of UTX in CD4+ T cells, we performed H3K27me3 CUT&Tag on CD4+ T cells isolated from B6.WT and B6.UTX TCD (Mice lacking UTX specifically in T cells) mice that were activated for 48 hours using plate-bound anti-CD3 and soluble anti-CD28.  Three mice per genotype were used in this experiment.