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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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KDM6 demethylase independent loss of histone H3 lysine 27 trimethylation during early embryonic development

ABSTRACT: H3K27me3 represses developmental genes at initial embryonic stages. The KDM6 family, comprised of UTX and JMJD3, are the only known proteins that demethylate H3K27me3 and they are hypothesized to catalyze the rapid removal of repressive chromatin in early mammalian development. However, we report that male embryos carrying mutations in both Utx and Jmjd3 survive to term and appear phenotypically normal at mid-gestation. We utilize several cell culture models to demonstrate that H3K27me3 is lost from repressed promoters in the absence of active KDM6 demethylation. Our data indicate that KDM6 H3K27me3 demethylation is not essential in the early embryo and that H3K27me3 loss from developmental genes occurs via novel mechanisms. Examination of 2 different histone modifications (H3K27me3 and H3K4me3) in 2 cell types (ES and retinoic acid treated ES cells) comparing WT to UTX and JMJD3 KOs. In ES cells, there are two WT replicates and two KO replicates, both measuring H3K27me3, and one replicate measuring input. In retinoic acid treatment, there are two replicates each for measuring H3K27me3 and H3K4me3 in WT and KO cell lines, and one replicate measuring input.

ORGANISM(S): Mus musculus

SUBMITTER: Joshua Starmer

PROVIDER: E-GEOD-58391 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner [ChIP-Seq data]

Project description:Embryogenesis requires the timely and coordinated activation of developmental regulators. It has been suggested that the recently discovered class of histone demethylases (UTX and JMJD3) that specifically target the repressive H3K27me3 modification play an important role in the activation of M-bM-^@M-^\bivalentM-bM-^@M-^] genes in response to specific developmental cues. To determine the requirements for UTX in pluripotency and development, we have generated Utx null ES cells and mutant mice. The loss of UTX had a profound effect during embryogenesis. Utx null embryos had reduced somite counts, neural tube closure defects and heart malformation which presented between E9.5 and E13.5. Unexpectedly, homozygous mutant female embryos were more severely affected than hemizygous mutant male embryos. In fact, we observed the survival of a subset of UTX-deficient males which were smaller in size and had reduced life-span. Interestingly, these animals were fertile with normal spermatogenesis. Consistent with a mid-gestation lethality, UTX null male and female ES cells gave rise to all three germ layers in teratoma assays although sex-specific differences could be observed in the activation of developmental regulators in embryoid body assays. Lastly, ChIP-seq analysis revealed an increase in H3K27me3 in Utx null male ES cells. In summary, our data demonstrate sex-specific requirements for this X-linked gene while suggesting a role for UTY during development. Examination of H3K27me3 and H3K4me3 in UtxKO ES cells (V6.5 background) vs UtxFlx (V6.5 background) ES cells grown in LIF containing ES cell media or treated with retinoic acid without LIF.

2012-08-01 | E-GEOD-39472 | biostudies-arrayexpress

The X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex specific manner [Agilent array data]

Project description:Embryogenesis requires the timely and coordinated activation of developmental regulators. It has been suggested that the recently discovered class of histone demethylases (UTX and JMJD3) that specifically target the repressive H3K27me3 modification play an important role in the activation of M-bM-^@M-^\bivalentM-bM-^@M-^] genes in response to specific developmental cues. To determine the requirements for UTX in pluripotency and development, we have generated Utx null ES cells and mutant mice. The loss of UTX had a profound effect during embryogenesis. Utx null embryos had reduced somite counts, neural tube closure defects and heart malformation which presented between E9.5 and E13.5. Unexpectedly, homozygous mutant female embryos were more severely affected than hemizygous mutant male embryos. In fact, we observed the survival of a subset of UTX-deficient males which were smaller in size and had reduced life-span. Interestingly, these animals were fertile with normal spermatogenesis. Consistent with a mid-gestation lethality, UTX null male and female ES cells gave rise to all three germ layers in teratoma assays although sex-specific differences could be observed in the activation of developmental regulators in embryoid body assays. Lastly, ChIP-seq analysis revealed an increase in H3K27me3 in Utx null male ES cells. In summary, our data demonstrate sex-specific requirements for this X-linked gene while suggesting a role for UTY during development. Keywords: Expression profiling by array Four-condition experiment, Wt (V6.5) ES vs. RA-treated Wt (V6.5) ES cells; UtxKO ES vs RA-treated UtxKO ES cells. This Series represents the Agilent microarray data only (not ChIP-Seq).

2012-07-31 | E-GEOD-39473 | biostudies-arrayexpress

Impact of Jmjd3 and Utx histone demethylases on Histone H3 lysine 27 trimethylation (H3K27Me3) in mature CD4 SP thymocytes

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2015-09-02 | E-GEOD-70795 | biostudies-arrayexpress

KDM6 demethylase independent loss of histone H3 lysine 27 trimethylation during early embryonic development

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2014-06-12 | GSE58391 | GEO

The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [ChIP-Seq]

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2012-05-30 | E-GEOD-37821 | biostudies-arrayexpress

Hira-dependent histone H3.3 deposition facilitates PRC2 recruitment at developmental loci in ES cells [ChIP-Seq]

Project description:Polycomb repressive complex 2 (PRC2) regulates gene expression during lineage specification through trimethylation of lysine 27 on histone H3 (H3K27me3). In Drosophila, polycomb binding sites are dynamic chromatin regions coupled to incorporation of the histone variant H3.3. Here we show in mouse embryonic stem cells (ESCs) that H3.3 is required for proper establishment of H3K27me3 at the promoters of developmentally regulated genes. These promoters show reduced dynamics as determined by deposition of de novo synthesized histones, associated with reduced PRC2 occupancy. H3.3-depleted ESCs show upregulation of extraembryonic trophectoderm, as well as misregulation of other developmental genes upon differentiation. Our data demonstrate the importance of H3.3 incorporation in ESCs and suggest that changes in chromatin dynamics in its absence lead to misregulation of gene expression during differentiation. Moreover, our findings lend support to the emerging notion that H3.3 has multiple functions in distinct genomic locations that are not always correlated with an “active” chromatin state. Native ChIP analysis of three histone post-translational modifications (H3K4me3, H3K27me3, H3K27ac) in two mouse embryonic stem cell (ESC) lines (control and H3.3-depleted). Inputs sequenced as control. Native ChIP analysis of H3.3B-HA in control and Suz12-/- ESCs. Crosslinking ChIP analysis of histone H3 using a general H3 antibody in two ESC lines (control and H3.3-depleted). Crosslinking ChIP analysis Hira, UTX, and Jmjd3 in wild type and H3.3 KO ESCs.

2013-09-30 | E-GEOD-42152 | biostudies-arrayexpress

The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [Affymetrix gene expression]

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

RNA-Sequencing of primary myoblasts from mice with a satellite cell specific knockout of the histone demthylase UTX/KDM6A

Project description:The KDM6 histone demethylases (UTX/KDM6A and JMJD3/KDM6B) mediate removal of repressive histone H3K27me3 marks to establish transcriptionally permissive chromatin. Loss of UTX in female mice is embryonic lethal. Unexpectedly, male UTX-null mice escape embryonic lethality due to expression of UTY, a paralog lacking H3K27-demethylase activity. This suggests that UTX plays an enzyme-independent role in development, and challenges the need for active H3K27-demethylation in vivo. However, the requirement for active H3K27-demethylation in stem cell-mediated tissue regeneration remains untested. Using an inducible mouse knockout that ablates UTX in satellite cells, we show that active H3K27-demethylation is necessary for muscle regeneration. Indeed, loss of UTX in satellite cells blocks myofiber regeneration in both male and female mice. Furthermore, we demonstrate that UTX mediates muscle regeneration through its H3K27-demethylase activity using a chemical inhibitor, and a demethylase-dead UTX knock-in mouse. Mechanistically, dissection of the muscle regenerative process revealed that UTX is required for expression of the transcription factor Myogenin that drives differentiation of muscle progenitors. Thus, we have identified a critical role for the enzymatic activity of UTX in activating muscle-specific gene expression during myofiber regeneration, revealing for the first time that active H3K27-demethylation has a physiological role in vivo. Satellite cells were sorted based on Cre-dependent expression of TdT reporter gene. Sorted UTXmKO or UTX WT satellite cells were then induced to differentiate for 24 hrs. RNA was then isolated and subjected to RNA-Seq analysis.

2016-03-22 | E-GEOD-69968 | biostudies-arrayexpress

H3K27me3 localization in UTX deficient Plasma cells by ChIP-seq

Project description:To evalute how deletion of H3K27me3 demethylases, UTX and JMJD3, affect H3K27me3 enrichment in plasma cells. ChIP-seq 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 | GSE185097 | GEO

UTX_CHIP_FIBROBLASTS

Project description:The recent discovery of a large number of histone demethylases suggests a central role for these enzymes in regulating histone methylation dynamics. Histone H3K27 trimethylation (H3K27me3) has been linked to Polycomb Group (PcG) protein-mediated suppression of Hox genes and animal body patterning, X-inactivation and possibly maintenance of embryonic stem (ES) cell identity. An imbalance of H3K27 methylation due to over-expression of the methylase EZH2 has been implicated in metastatic prostate and aggressive breast cancers. Here we show that the related JmjC domain-containing UTX and JMJD3 catalyze demethylation of H3K27me3. UTX is enriched around the transcription start sites of many Hox genes in primary human fibroblasts where Hox genes are differentially expressed, but is selectively excluded from the Hox locus in ES cells in which Hox genes are largely silent. Consistently, RNAi inhibition of UTX led to increased H3K27me3 levels at some Hox gene promoters. Importantly, Morpholino inhibition of a zebrafish UTX homolog resulted in mis-regulation of Hox genes and a striking posterior developmental defect, which was partially rescued by wildtype, but not catalytically inactive human UTX. Taken together, these findings identified a small family of H3K27 demethylases with important, evolutionarily conserved roles in H3K27 methylation regulation and in animal anterior-posterior development. Keywords: organism_part_comparison_design

2007-09-07 | GSE8855 | GEO

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