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An essential role for UTX in resolution and activation of bivalent promoters

ABSTRACT: In the present study, we show that UTX plays an essential role in resolving and activating many retinoic acid (RA)-inducible bivalent genes during the RA-driven differentiation of mouse ESCs treated with a physiologically relevant RA concentration (0.2 μM). We showed that UTX loss and UTX knockdown interfered with the RA-induced differentiation of mouse ESCs. Therefore, our findings indicate that the UTX-mediated resolution and activation of many RA-inducible bivalent genes, including numerous Hoxa-d cluster genes, are required for RA-driven differentiation of mouse ESCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE76692 | GEO | 2016/02/05

SECONDARY ACCESSION(S): PRJNA308325

REPOSITORIES: GEO

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An essential role for UTX in resolution and activation of bivalent promoters

Project description:In the present study, we show that UTX plays an essential role in resolving and activating many retinoic acid (RA)-inducible bivalent genes during the RA-driven differentiation of mouse ESCs treated with a physiologically relevant RA concentration (0.2 Î¼M). We showed that UTX loss and UTX knockdown interfered with the RA-induced differentiation of mouse ESCs. Therefore, our findings indicate that the UTX-mediated resolution and activation of many RA-inducible bivalent genes, including numerous Hoxa-d cluster genes, are required for RA-driven differentiation of mouse ESCs. ChIP-Seq data for H3K4me3 and H3K27me3 were generated along with input data for mouse stem cells with wild type or UTX-depleted genotype and with or without RA treatment.

2016-02-05 | E-GEOD-76692 | biostudies-arrayexpress

Utx interactome in mouse myeloid progenitor cells

Project description:Immunoprecipitation of Utx followed by mass spectrometry analysis to identify Utx binding partners in mouse myeloid progenitor cells.

2018-04-30 | PXD005011 | Pride

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

Mammalian Dpy-30 regulates genomic H3K4 methylation and is essential for ES cell fate specification

Project description:H3K4 methylation is associated with active genes and, along with H3K27 methylation, is part of a bivalent chromatin mark that typifies poised developmental genes in ESCs. However, its functional roles in ESC maintenance and differentiation are not established. Here we show that mammalian Dpy-30, a core subunit of SET1/MLL complexes, biochemically modulates H3K4 methylation in vitro, and directly regulates chromosomal H3K4me3 throughout the mammalian genome. Depletion of Dpy-30 does not affect ESC self-renewal, but significantly alters the differentiation potential of ESCs, particularly along the neural lineage. The differentiation defect is accompanied by defects in gene induction and H3K4 methylation at key developmental loci. Our results provide strong experimental evidence for the hypothesis that H3K4 methylation is an essential functional component of the bivalent mark during activation of developmental genes in ESCs. Total RNAs from control or knockdown cells before and after RA-mediated differentiation were subjected to Illumina microarray analyses. ChIP-enriched DNA from mouse ES cells was analyzed by Solexa sequencing.

2011-02-01 | E-GEOD-26136 | biostudies-arrayexpress

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

2016-03-22 | GSE69968 | GEO

HNF1A, UTX, H3K27me3 and H3K27ac ChIP-seq in wild-type and UTX- or HNF1A-deficient mouse pancreas

Project description:HNF1A and UTX are putative tumor suppressors in pancreatic cancer. In this study, we have combined mouse genetics, transcriptomics and genome binding studies to link HNF1A and UTX in a molecular mechanism that suppresses pancreatic cancer. In this session, we have profiled UTX, HNF1A, H3K27me3 and H3K27ac in normal and UTX- or HNF1A-deficient mouse pancreas by ChIP-seq experiments. We show that HNF1A recruits UTX to its genomic targets in pancreatic acinar cells, which results in remodeling of the chromatin landscape and activation of a broad transcriptional program of differentiated acinar cells, which in turn indirectly suppresses tumor suppressor pathways.

2019-12-20 | E-MTAB-7944 | biostudies-arrayexpress

Alternative mRNA splicing controls functions of the human H3K27 demethylase UTX/KDM6A

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

UTX Regulates Human Neural Differentiation and Dendritic Morphology by Resolving Bivalent Promoters

Project description:UTX Regulates Human Neural Differentiation and Dendritic Morphology by Resolving Bivalent Promoters

| PRJNA639440 | ENA

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

Characterizing the contrasting roles of JMJD3 and UTX histone demethylases in T cell acute lymphoblastic leukemia [UTXKO_RNA-seq]

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we conduct expression analysis in NOTCH1-IC-induced tumors in Utx wild-type (Utx+/+ or Utx+/Y) and knockout (Utx-/Y) background. These results, coupled to genomic analysis of primary samples for the genomic status of the UTX gene in T-ALL, helped us to characterize the hitherto understudied role of Utx as an oncogenic facilitator in leukemia and the contrasting expression signatures between JMJD3 and UTX in this disease. Whole RNA was extracted from 1-5 million primary cells from Notch1-IC-expressing (sorted populations of) mouse T-ALL tumors using the RNAeasy kit (Qiagen) according to the manufacturer’s protocol. Poly-A+ (magnetic oligodT-containing beads (Invitrogen)) or Ribominus RNA was used for library preparation. cDNA preparation and strand-specific library construction was performed using the dUTP method. Libraries were sequenced on the Illumina HiSeq 2000 using 50bp single-read method. Differential gene expression analysis was performed between knockout vs wild-type background samples. Analysis was performed using DEGseq package leading to very similar conclusions.

2014-10-01 | E-GEOD-56690 | biostudies-arrayexpress

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