The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE37822 | GEO | 2012/05/30
SECONDARY ACCESSION(S): PRJNA163901
REPOSITORIES: GEO
Similar Datasets
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:Pluripotency can be induced in somatic cells by ectopic expression of defined transcription factors, however the identity of epigenetic regulators driving the progression of cellular reprogramming requires further investigation. Here we uncover a non-redundant role for the JmjC-domain-containing protein histone H3 methylated Lys 27 (H3K27) demethylase Utx, as a critical regulator for the induction, but not for the maintenance, of primed and naM-CM-/ve pluripotency in mice and in humans. Utx depletion results in aberrant H3K27me3 repressive chromatin demethylation dynamics, which subsequently hampers the reactivation of pluripotency promoting genes during reprogramming. Remarkably, Utx deficient primordial germ cells (PGCs) display a cell autonomous aberrant epigenetic reprogramming in vivo during their embryonic maturation, resulting in the lack of functional contribution to the germ-line lineage. H3K27me3 and H3K4me3 were measured genome-wide in the following cell types: Utx+/Y (WT) and Utx-/Y (KO) mouse ES cells and mouse embryonic fibroblast (MEF) before and after DOX induction (initiating reprogramming by OSKM factors).
2012-05-30 | E-GEOD-37821 | biostudies-arrayexpress
Project description:Pluripotency can be induced in somatic cells by ectopic expression of defined transcription factors, however the identity of epigenetic regulators driving the progression of cellular reprogramming requires further investigation. Here we uncover a non-redundant role for the JmjC-domain-containing protein histone H3 methylated Lys 27 (H3K27) demethylase Utx, as a critical regulator for the induction, but not for the maintenance, of primed and naM-CM-/ve pluripotency in mice and in humans. Utx depletion results in aberrant H3K27me3 repressive chromatin demethylation dynamics, which subsequently hampers the reactivation of pluripotency promoting genes during reprogramming. Remarkably, Utx deficient primordial germ cells (PGCs) display a cell autonomous aberrant epigenetic reprogramming in vivo during their embryonic maturation, resulting in the lack of functional contribution to the germ-line lineage. Samples include UTX+/Y (WT) and UTX-/Y (KO) cells from mouse ES cells and mouse embryonic fibroblast (MEF) before and after DOX induction (initiating reprogramming by OSKM factors). One sample is OSKM-induced Nanog-/- fibroblasts.
2012-05-29 | E-GEOD-35775 | biostudies-arrayexpress
Project description:Pluripotency can be induced in somatic cells by ectopic expression of defined transcription factors, however the identity of epigenetic regulators driving the progression of cellular reprogramming requires further investigation. Here we uncover a non-redundant role for the JmjC-domain-containing protein histone H3 methylated Lys 27 (H3K27) demethylase Utx, as a critical regulator for the induction, but not for the maintenance, of primed and naïve pluripotency in mice and in humans. Utx depletion results in aberrant H3K27me3 repressive chromatin demethylation dynamics, which subsequently hampers the reactivation of pluripotency promoting genes during reprogramming. Remarkably, Utx deficient primordial germ cells (PGCs) display a cell autonomous aberrant epigenetic reprogramming in vivo during their embryonic maturation, resulting in the lack of functional contribution to the germ-line lineage.
2012-05-30 | GSE37821 | GEO
Project description:Pluripotency can be induced in somatic cells by ectopic expression of defined transcription factors, however the identity of epigenetic regulators driving the progression of cellular reprogramming requires further investigation. Here we uncover a non-redundant role for the JmjC-domain-containing protein histone H3 methylated Lys 27 (H3K27) demethylase Utx, as a critical regulator for the induction, but not for the maintenance, of primed and naïve pluripotency in mice and in humans. Utx depletion results in aberrant H3K27me3 repressive chromatin demethylation dynamics, which subsequently hampers the reactivation of pluripotency promoting genes during reprogramming. Remarkably, Utx deficient primordial germ cells (PGCs) display a cell autonomous aberrant epigenetic reprogramming in vivo during their embryonic maturation, resulting in the lack of functional contribution to the germ-line lineage.
2012-05-30 | GSE35775 | GEO
Project description:Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene.
| S-EPMC2873835 | biostudies-literature
Project description:We describe inactivating somatic mutations in the histone lysine demethylase, UTX, in human cancers pointing to the deregulation of histone H3 lysine methylation in the development of multiple tumour types. Gene expression was analysed on Illumina Human WG-6 v2 BeadChips following standard protocols. Data quality test and normalization were performed using the Lumi package implemented in R.
| S-ECPF-MTAB-84 | biostudies-other
Project description:The processes mediating the repair of DNA double-strand breaks (DSB) are critical determinants of radiosensitivity and provide a source of potential targets for tumor radiosensitization. Among the events required for efficient DSB repair are a variety of post-translational histone modifications, including methylation. Because trimethylation of histone H3 on lysine 27 (H3K27me3) has been associated with chromatin condensation, which can influence DSB repair, we determined the effects of radiation on H3K27me3 levels in tumor and normal cell lines. Irradiation of tumor cells resulted in a rapid loss of H3K27me3, which was prevented by the siRNA-mediated knockdown of the H3K27 demethylase UTX. Knockdown of UTX also enhanced the radiosensitivity of each tumor cell line. Treatment of tumor cells with the H3K27 demethylase inhibitor GSKJ4 immediately before irradiation prevented the radiation-induced decrease in H3K27me3 and enhanced radiosensitivity. As determined by neutral comet analysis and γH2AX expression, this GSKJ4 treatment protocol inhibited the repair of radiation-induced DSBs. Consistent with in vitro results, treatment of mice bearing leg tumor xenografts with GSKJ4 significantly enhance radiation-induce tumor growth delay. In contrast with results generated from tumor cell lines, radiation had no effect on H3K27me3 levels in normal fibroblast cell lines and GSKJ4 did not enhance their radiosensitivity. These data suggest that H3K27me3 demethylation contributes to DSB repair in tumor cells and that UTX, the demethylase responsible, provides a target for selective tumor cell radiosensitization. Mol Cancer Ther; 17(5); 1070-8. ©2018 AACR.
| S-EPMC5932086 | biostudies-literature
Project description:Understanding the molecular mechanisms that drive adipogenesis is important in developing new treatments for obesity and diabetes. Epigenetic regulations determine the capacity of adipogenesis. In this study, we examined the role of a histone H3 lysine 27 demethylase, the ubiquitously transcribed tetratricopeptide repeat protein on the X chromosome (Utx), in the differentiation of mouse embryonic stem cells (mESCs) to adipocytes. Using gene trapping, we examined Utx-deficient male mESCs to determine whether loss of Utx would enhance or inhibit the differentiation of mESCs to adipocytes. Utx-deficient mESCs showed diminished potential to differentiate to adipocytes compared to that of controls. In contrast, Utx-deficient preadipocytes showed enhanced differentiation to adipocytes. Microarray analyses indicated that the β-catenin/c-Myc signaling pathway was differentially regulated in Utx-deficient cells during adipocyte differentiation. Therefore, our data suggest that Utx governs adipogenesis by regulating c-Myc in a differentiation stage-specific manner and that targeting the Utx signaling pathway could be beneficial for the treatment of obesity, diabetes, and congenital utx-deficiency disorders.
| S-EPMC5358847 | biostudies-literature
Project description:Epigenome alteration in chondrocytes correlates with osteoarthritis (OA) development. H3K27me3 demethylase UTX regulates tissue homeostasis and deterioration, while its role was not yet studied in articulating joint tissue in situ. We now uncovered that increased UTX and H3K27me3 expression in articular chondrocytes positively correlated with human knee OA. Forced UTX expression upregulated the H3K27me3 enrichment at transcription factor Sox9 promoter, inhibiting key extracellular matrix molecules collagen II, aggrecan, and glycosaminoglycan in articular chondrocytes. Utx overexpression in knee joints aggravated the signs of OA, including articular cartilage damage, synovitis, osteophyte formation, and subchondral bone loss in mice. Chondrocyte-specific Utx knockout mice developed thicker articular cartilage than wild-type mice and showed few gonarthrotic symptoms during destabilized medial meniscus- and collagenase-induced joint injury. In vitro, Utx loss changed H3K27me3-binding epigenomic landscapes, which contributed to mitochondrial activity, cellular senescence, and cartilage development. Insulin-like growth factor 2 (Igf2) and polycomb repressive complex 2 (PRC2) core components Eed and Suz12 were, among others, functional target genes of Utx. Specifically, Utx deletion promoted Tfam transcription, mitochondrial respiration, ATP production and Igf2 transcription but inhibited Eed and Suz12 expression. Igf2 blockade or forced Eed or Suz12 expression increased H3K27 trimethylation and H3K27me3 enrichment at Sox9 promoter, compromising Utx loss-induced extracellular matrix overproduction. Taken together, UTX repressed articular chondrocytic activity, accelerating cartilage loss during OA. Utx loss promoted cartilage integrity through epigenetic stimulation of mitochondrial biogenesis and Igf2 transcription. This study highlighted a novel noncanonical role of Utx, in concert with PRC2 core components, in controlling H3K27 trimethylation and articular chondrocyte anabolism and OA development.
| S-EPMC9178009 | biostudies-literature