RNA-seq analysis of Kdm6a deficient brains in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE81251 | GEO | 2017/05/06
SECONDARY ACCESSION(S): PRJNA321062
REPOSITORIES: GEO
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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:Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus, and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/βGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/βGeo mice modulates H3ac and H3K4me3 in the granular cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/βGeo mice; similar effects on neurogenesis were observed upon exogenous administration of beta-hydroxybutyrate. These data suggests that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders. We used microarrays to query global gene expression changes in the hippocampus of wild type and Kmt2d+/βGeo (Kabuki syndrome model) mice on a regular diet to identify specific gene expression abnormalities in the hippocampus of the Kabuki syndrome mouse model.
2016-12-03 | GSE90836 | 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:BACKGROUND & AIMS: Although genomic analysis have recently discovered the malignant subtype of human pancreatic ductal adenocarcinoma (PDAC) characterized by frequent mutations of a histone modifier KDM6A, the biological and molecular roles still remain obscure. We herein elucidated the clinical and biological impacts of KDM6A deficiency on human PDAC and identified the therapeutic potential by pathological and molecular evaluation. METHODS: Immunohistochemical analysis of KDM6A was performed in 103 tumor specimens surgically resected from patients with PDAC. Cells knocked out for KDM6A by using the CRISPR/Cas9 system and expressing doxycycline-inducible KDM6A were established from each two human PDAC cell lines, respectively. RESULTS: Loss of KDM6A in cancerous tissues was an independent prognostic factor for both recurrence-free and overall survival in the clinical samples. KDM6A knockout enhanced aggressive traits of human PDAC cell lines, whereas KDM6A overexpression suppressed them. Microarray analysis revealed reduced expression of 25 genes including five well-known tumor suppressors, such as CDKN1A, and ChIP-PCR analysis displayed depleted enrichment of histone H3 lysine 27 acetylation (H3K27ac) at the promoter regions of the five candidates. The epigenetic alterations were induced by the impaired recruitment of a histone acetyltransferase p300, which cooperatively interacted with KDM6A. Consistent with these results, the KDM6A knockout cells demonstrated higher vulnerability to histone deacetylase (HDAC) inhibitors through the reactivation of CDKN1A in vitro and in vivo than the KDM6A wild-type. CONCLUSIONS: KDM6A exhibited essential roles in human PDAC as a tumor suppressor. KDM6A deficiency could be a promising biomarker for unfavorable outcome in PDAC patients and a potential surrogate marker for response to HDAC inhibitors.
2020-01-30 | GSE114457 | GEO
Project description:Large-scale genome sequencing efforts of human tumors identified epigenetic modifiers as one of the most frequently mutated gene class in human cancer. However, how these mutations drive tumor development and progression is largely unknown. Here, we identify the histone demethylase KDM6A as an important tumor suppressor in solid cancers, such as liver cancer and pancreatic cancer. KDM6A-deficient tumors show hyperactivation of mTORC1 signaling, whereas endogenous KDM6A re-expression in established KDM6A-deficient tumors diminishes mTORC1 activity by fostering the expression of crucial negative pathway regulators, such as DEPTOR, TSC1, and TSC2, resulting in tumor regression. Importantly, KDM6A expression in human tumors correlates with mTORC1 activity and KDM6A-deficient tumors exhibit increased sensitivity to mTORC1 inhibition. Hence, our results link KDM6A-dependent epigenetic remodeling to mTORC1 signaling and provide a potential therapeutic strategy for KDM6A-deficient tumors.
2022-07-20 | GSE155630 | GEO
Project description:KDM6A, which regulates gene expression by demethylation of the repressive histone mark H3K27me3, has a higher level in mammalian females than in males because the Kdm6a gene escapes X chromosome inactivation. Here, we report that maternal and paternal alleles of a number of genes throughout the genome are differentially regulated by KDM6A. Knockout of KDM6A in male and female embryonic stem cells derived from F1 hybrid mice results in downregulation of maternal alleles more frequently than paternal alleles. This parent-of-origin preference for regulation of gene expression by KDM6A was observed for subsets of maternally expressed non-imprinted and imprinted genes. By ATAC-seq downregulated genes showed a concomitant loss of chromatin accessibility on maternal but not on paternal alleles. Surprisingly, enrichment in H3K27me3 was observed on downregulated paternal but not maternal alleles. These results suggest parent-of-origin mechanisms of gene regulation by KDM6A, which may be histone demethylation-dependent and -independent.
2022-07-26 | GSE209788 | GEO
Project description:KDM6A, which regulates gene expression by demethylation of the repressive histone mark H3K27me3, has a higher level in mammalian females than in males because the Kdm6a gene escapes X chromosome inactivation. Here, we report that maternal and paternal alleles of a number of genes throughout the genome are differentially regulated by KDM6A. Knockout of KDM6A in male and female embryonic stem cells derived from F1 hybrid mice results in downregulation of maternal alleles more frequently than paternal alleles. This parent-of-origin preference for regulation of gene expression by KDM6A was observed for subsets of maternally expressed non-imprinted and imprinted genes. By ATAC-seq downregulated genes showed a concomitant loss of chromatin accessibility on maternal but not on paternal alleles. Surprisingly, enrichment in H3K27me3 was observed on downregulated paternal but not maternal alleles. These results suggest parent-of-origin mechanisms of gene regulation by KDM6A, which may be histone demethylation-dependent and -independent.
2022-07-26 | GSE209787 | GEO
Project description:KDM6A, which regulates gene expression by demethylation of the repressive histone mark H3K27me3, has a higher level in mammalian females than in males because the Kdm6a gene escapes X chromosome inactivation. Here, we report that maternal and paternal alleles of a number of genes throughout the genome are differentially regulated by KDM6A. Knockout of KDM6A in male and female embryonic stem cells derived from F1 hybrid mice results in downregulation of maternal alleles more frequently than paternal alleles. This parent-of-origin preference for regulation of gene expression by KDM6A was observed for subsets of maternally expressed non-imprinted and imprinted genes. By ATAC-seq downregulated genes showed a concomitant loss of chromatin accessibility on maternal but not on paternal alleles. Surprisingly, enrichment in H3K27me3 was observed on downregulated paternal but not maternal alleles. These results suggest parent-of-origin mechanisms of gene regulation by KDM6A, which may be histone demethylation-dependent and -independent.
2022-07-26 | GSE209786 | GEO
Project description:As a histone hallmark for transcription repression, Histone H3 lysine 27 trimethylation (H3K27me3) plays important roles in mammalian embryo development and induced pluripotent stem cells (iPSCs) generation. However, the expression profile and roles of H3K27me3 in bovine somatic cell nuclear transfer (SCNT) reprogramming remain poorly understood. In this study, we find SCNT embryos exhibit global hypermethylation of H3K27me3 from two-cell to eight-cell stage and its removal by ectopically expressed H3K27me3 demethylase-KDM6A could greatly improves SCNT efficiency. To illuminate the mechanism of improving SCNT reprogramming efficiency of KDM6A overexpression, we performed RNA sequencing of transcripts in SCNT morula with or without KDM6A overexpression. RNA-seq reveal that KDM6A overexpression could enhance transcription of genes mainly involved cell adhesion and cellular metabolism process, as well as X-linked genes. We first provides the transcriptome data of bovine SCNT morula with or without KDM6A overexpression. Meanwhile, we compared the differences of transcriptome between SCNT eight-cell embryos and morula. Our study provide a more promising approach to improving the efficiency of SCNT reprogramming and contribute to understanding the mechanism of first cell fate determine during embryo development in bovine.
2019-01-31 | GSE114596 | 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.
2013-03-22 | GSE45390 | GEO