Similar Datasets
Project description:Kdm6a suppresses the alternative activation of macrophages
| PRJNA644806 | 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:X chromosome inactivation (XCI) is a female-specific process in which one X chromosome is silenced to balance X-linked gene expression between the sexes. XCI is initiated in early development by upregulation of the lncRNA Xist on the future inactive X (Xi). A subset of X-linked genes escape silencing and thus have higher expression in females, suggesting female-specific functions. One of these genes is the highly conserved gene Kdm6a, which encodes a histone demethylase that removes methyl groups at H3K27 to facilitate gene expression. Here, we investigate the role of KDM6A in the regulation of Xist. We observed impaired upregulation of Xist during early stages of differentiation in hybrid mouse ES cells following CRISPR/Cas9 knockout of Kdm6a. This is associated with reduced Xist RNA coating of the Xi, suggesting diminished XCI potency. Indeed, Kdm6a knockout results in aberrant overexpression of genes from the Xi after differentiation. KDM6A binds to the Xist promoter and knockout cells show an increase in H3K27me3 at Xist. These results indicate that KDM6A plays a role in the initiation of XCI through histone demethylase-dependent activation of Xist during early differentiation.
2025-01-08 | GSE279279 | GEO
Project description:X chromosome inactivation (XCI) is a female-specific process in which one X chromosome is silenced to balance X-linked gene expression between the sexes. XCI is initiated in early development by upregulation of the lncRNA Xist on the future inactive X (Xi). A subset of X-linked genes escape silencing and thus have higher expression in females, suggesting female-specific functions. One of these genes is the highly conserved gene Kdm6a, which encodes a histone demethylase that removes methyl groups at H3K27 to facilitate gene expression. Here, we investigate the role of KDM6A in the regulation of Xist. We observed impaired upregulation of Xist during early stages of differentiation in hybrid mouse ES cells following CRISPR/Cas9 knockout of Kdm6a. This is associated with reduced Xist RNA coating of the Xi, suggesting diminished XCI potency. Indeed, Kdm6a knockout results in aberrant overexpression of genes from the Xi after differentiation. KDM6A binds to the Xist promoter and knockout cells show an increase in H3K27me3 at Xist. These results indicate that KDM6A plays a role in the initiation of XCI through histone demethylase-dependent activation of Xist during early differentiation.
2025-01-08 | GSE279278 | GEO
Project description:This study reports that CAFs isolated from colon cancer tissue, TGF-β1-induced CAFs, or HCT116 co-cultured CAFs secrete more cytokines and growth factors represented by IGF1, ELN, and SFRP2. Mechanistic investigations demonstrate that aerobic glycolysis metabolites fumarate and succinate can induce the transcription of IGF1, ELN, and SFRP2 in CAFs, while α-ketoglutarate (α-KG) can antagonize the induction effect of fumarate and succinate. Moreover, the downregulation of KDM6A in CAFs is observed compared to quiescent fibroblasts (NAFs). Additionally, integrated analysis of ATAC sequencing and RNA sequencing revealed altered chromatin structure during fibroblast activation. CUT-tag sequencing and co-IP assays demonstrate that KDM6A is bound to WDR5, facilitating its association with the COMPASS complex and the polycomb repressive complex at the expected target loci. Depletion of KDM6A disrupts the homeostasis between polycomb and COMPASS complexes, leading to an increase in the expression of IGF1, ELN, and SFRP2. However, the inhibitor GSK-J4 specific for both KDM6A and KDM6B reduces IGF1 expression, indicating that KDM6B compensates for the demethylase function of KDM6A but cannot replace KDM6A to maintain the homeostasis of COMPASS and polycomb repressive complexes. These findings suggest a metabolism-related epigenetic mechanism for cytokine expression, where reduced KDM6A levels enhance the tumor-promoting effect of CAFs. This may provide insights into why colon cancer is more prevalent in men than in women since KDM6A is an X-chromosome-associated gene.
2025-07-23 | GSE283546 | GEO
Project description:Here we show binding and occupancy profiles for KDM6A, H3K27me3 and H3K4me3 to address the epigenetic regulation of a subset of Rhox genes, Rhox6 and 9, in female and male ES cells during differentiation. To further address a functional role for KDM6A in the epigenetic regulation of Rhox6 and 9, binding profiles for female ES cells treated with a control siRNA and siRNA specific for Kdm6a are shown. We report that two members of the Rhox cluster, Rhox6 and 9, are regulated by de-methylation of histone H3 at lysine 27 by KDM6A, a histone demethylase with female-biased expression. Our results are consistent with other homeobox genes in that Rhox6 and 9 are in bivalent domains prior to embryonic stem cell differentiation and thus poised for activation. In female mouse ES cells KDM6A is specifically recruited to Rhox6 and 9 for gene activation, a process inhibited by Kdm6a knockdown. In contrast, KDM6A occupancy at Rhox6 and 9 is low in male ES cells and knockdown has no effect on expression. Our study implicates Kdm6a, a gene that escapes X inactivation, in the regulation of genes important in reproduction, suggesting that KDM6A may play a role in the etiology of developmental and reproduction-related effects of X chromosome anomalies. ChIP-chip was used to analyze the binding profiles of KDM6A, H3K27me3, and H3K4me3 during differentiation in female and male ES cells. Additionally, ChiP-chip of KDM6A binding in control treated and siRNA treated ES cells is presented.
2013-03-22 | E-GEOD-45390 | biostudies-arrayexpress
Project description:Purpose: The goals of this study are to compare 1. The transcription profile in KDM6A wildtype and KDM6A mutated urothelial bladder carcinoma. 2. The transcriptional changes in KDM6A mutated urothelial bladder carcinoma upon EZH2 inhibitor treatment.
2017-03-01 | GSE92723 | GEO
Project description:Mammary ducts and alveoli are composed of basal and luminal cells, with the fate and differentiation of secreting cells being controlled by hormones through specific transcription factors. This study establishes the essential role of the histone H3 lysine 27 trimethylation (H3K27me3) demethylase KDM6A (UTX) in a balanced basal and luminal cell compartment. Disproportionate formation of basal cells in the absence of KDM6A resulted in disorganized mammary ducts and alveoli and lactation failure. Mutant luminal progenitors lost their distinctive transcription factor expression pattern and acquired basal characteristics leading to a preferential expansion of this lineage. The structure of mammospheres obtained from mutant progenitors suggested they were derived from basal progenitors. The genomic H3K27me3 landscape was unaltered in the absence of KDM6A suggesting demethylase-independent mechanisms. In support of this, mammary tissue developed normally in mice expressing a catalytically inactive KDM6A. This study demonstrated that mammary luminal progenitor cells rely on UTX to stably maintain their identity and thereby establish a balance of basal and luminal cells required for a functional mammary gland.
2016-06-06 | GSE77586 | GEO
Project description:Histone lysine demethylase 6a (Kdm6a) mediates the removal of repressive trimethylation from histone H3 lysine 27 (H3K27me3) to activate target gene expression. Obesity is associated with metabolic inflammation, and adipose tissue macrophages (ATMs) are key players orchestrating metabolic inflammation. However, it is still unclear whether the Kdm6a pathway in ATMs regulates energy homeostasis. Here, we identified Kdm6a as a critical epigenetic switch that modulates macrophage polarisation and further disrupts energy balance. Myeloid-specific Kdm6a knockout in Kdm6aF/Y;Lyz2-Cre mice significantly reversed the high-fat diet (HFD)-induced M1-M2 imbalance in white adipose tissue (WAT) and blocked HFD-induced obesity. The brown adipose tissue (BAT) activity, WAT browning and energy expenditure were significantly increased in Kdm6aF/Y;Lyz2-Cre mice. Furthermore, Kdm6a regulated the Ire1α expression in a demethylase activity-dependent manner and augmented the M2 polarisation of macrophages. Macrophage with higher Kdm6a significantly promotes adipogenesis in white adipocyte and inhibits thermogenesis in beige adipocytes. These results suggest that the Kdm6a in macrophages drives obesity and metabolic syndrome by impairing BAT activity and WAT differentiation.
| S-EPMC8167088 | biostudies-literature
Project description:We created isogenic mutiple myeloma and mouse embryonic fibroblast cell lines disrupted for KDM6A using CRISPR editing and Cre-mediated deletion. To detect KDM6A we inserted a dual HA tag sequence into the C-terminal of KDM6A by CRISPR-mediated editing. We also created one isogenic cell line harboring a jmjD-dead KDM6A where 2 amino acids essential for KDM6A enzymatic activity, H1146 and E1148 , were replaced with alanine residues
2024-10-01 | GSE244510 | GEO