Hypoxia-sensing by Colitogenic CD4+ T cells Is Regulated by the Histone Demethylase UTX [H3K27me3 CUT&Tag]
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ABSTRACT:
PROVIDER: PRJNA989647 | ENA |
REPOSITORIES: ENA
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Project description: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-γ 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.
2023-12-01 | GSE236300 | GEO
Project description:Hypoxia-sensing by Colitogenic CD4+ T cells Is Regulated by the Histone Demethylase UTX.
| PRJNA989641 | ENA
Project description: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-γ 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.
2023-12-01 | GSE236299 | GEO
Project description:Hypoxia-sensing by Colitogenic CD4+ T cells Is Regulated by the Histone Demethylase UTX [RNA-seq]
| PRJNA989646 | ENA
Project description:The UTX/KDM6A gene encodes the UTX histone H3K27 demethylase, which plays an important role in mammalian development and is frequently mutated in cancers and particularly, in urothelial cancers. Using BioID technique, we explored the interactome of different UTX isoforms.
2024-01-28 | PXD041254 | Pride
Project description:This SuperSeries is composed of the following subset Series: GSE39472: X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner [ChIP-Seq data] GSE39473: The X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex specific manner [Agilent array data] Refer to individual Series
2012-07-31 | E-GEOD-39222 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE35775: The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [Affymetrix gene expression] GSE37821: The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [ChIP-Seq] Refer to individual Series
2012-05-29 | E-GEOD-37822 | biostudies-arrayexpress
Project description:Metformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure- and ligand-based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3-specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low-density lipoprotein receptor-deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft-bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.
| S-EPMC6052472 | biostudies-literature
Project description:Kabuki syndrome (KS) is a rare multiple congenital anomalies/mental retardation (MCA/MR) syndrome described in 19811,2. In 2010, exome sequencing identified MLL2 mutations in patients with KS3. Since then, 5 studies identified a mutation in MLL2 in 56-75,6% of KS patients3-7. Here, we describe 2 KS and 1 KS-like patient with a de novo partial or complete deletion of UTX, a histone demethylase interacting with MLL2 in gene regulation. UTX locates on the X chromosome and we showed that the X chromosome with the deleted copy of UTX is preferentially inactivated despite the fact that UTX escapes X-inactivation. This study unveiled deletion of UTX as a second cause of KS and highlights the growing role of histone methylase/demethylase in MCA/MR syndrome. Two patients were analysed by Agilent array CGH 244K (AMADID: 014693) Three patients DNA were analyzed by CGH on custom targeted array 44K (AMADID: 032482). Two of them were initially analyzed using 244K Whole genome Arrays (AMADID: 014693). One third patient was selected given suspicion of deletion in one of the targeted gene (KDM6A) as amplification of some exons performed in our lab to sequence this gene failed.
2012-01-01 | E-GEOD-32567 | biostudies-arrayexpress
Project description:To understand the role of the H3K27me3 demethylases, UTX and JMJD3, in B cell differentiation. CUT&Tag for H3K27me3 was performed on CreCtrl and dKO (UTX and JMJD3-deficient) PC at day three post in vivo stimulation with LPS.
2022-02-01 | GSE185098 | GEO