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UTX-mediated chromatin remodeling suppresses myeloid leukaemogenesis through non-catalytic inverse regulation of ETS and GATA transcriptional programs (ATAC-Seq)

ABSTRACT: The H3K27 lysine-specific demethylase UTX is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukaemogenesis through non-catalytic functions, a property it shares with its catalytically inactive Y-chromosome paralogue, UTY. In keeping with this, we demonstrate concomitant loss/mutation of UTX and UTY in multiple human cancers. Mechanistically, global genomic profiling revealed only minor changes in H3K27Me3, but significant and bidirectional alterations of H3K27Ac and chromatin accessibility, alterations in ETS and GATA factor binding and altered gene expression upon Utx loss. By integrating proteomic and genomic analyses, we link these changes to UTX coordination of ATP-dependent chromatin remodelling and competition between UTX and ETS factors for binding at critical DNA-sequences. Collectively, our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via inhibition of oncogenic ETS and upregulation of tumour-suppressive GATA programmes. We propose that equivalent changes in tissue-specific oncogenic and tumour-suppressive transcriptional programmes operate in other UTX-mutated cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE86489 | GEO | 2018/05/01

REPOSITORIES: GEO

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UTX-mediated chromatin remodeling suppresses myeloid leukaemogenesis through non-catalytic inverse regulation of ETS and GATA transcriptional programs (ChIP-Seq)

Project description:The H3K27 lysine-specific demethylase UTX is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukaemogenesis through non-catalytic functions, a property it shares with its catalytically inactive Y-chromosome paralogue, UTY. In keeping with this, we demonstrate concomitant loss/mutation of UTX and UTY in multiple human cancers. Mechanistically, global genomic profiling revealed only minor changes in H3K27Me3, but significant and bidirectional alterations of H3K27Ac and chromatin accessibility, alterations in ETS and GATA factor binding and altered gene expression upon Utx loss. By integrating proteomic and genomic analyses, we link these changes to UTX coordination of ATP-dependent chromatin remodelling and competition between UTX and ETS factors for binding at critical DNA-sequences. Collectively, our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via inhibition of oncogenic ETS and upregulation of tumour-suppressive GATA programmes. We propose that equivalent changes in tissue-specific oncogenic and tumour-suppressive transcriptional programmes operate in other UTX-mutated cancers.

2018-05-01 | GSE86488 | GEO

UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs

Project description:The histone H3 Lys27-specific demethylase UTX (or KDM6A) is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukemogenesis through noncatalytic functions, a property shared with its catalytically inactive Y-chromosome paralog, UTY (or KDM6C). In keeping with this, we demonstrate concomitant loss/mutation of KDM6A (UTX) and UTY in multiple human cancers. Mechanistically, global genomic profiling showed only minor changes in H3K27me3 but significant and bidirectional alterations in H3K27ac and chromatin accessibility; a predominant loss of H3K4me1 modifications; alterations in ETS and GATA-factor binding; and altered gene expression after Utx loss. By integrating proteomic and genomic analyses, we link these changes to UTX regulation of ATP-dependent chromatin remodeling, coordination of the COMPASS complex and enhanced pioneering activity of ETS factors during evolution to AML. Collectively, our findings identify a dual role for UTX in suppressing acute myeloid leukemia via repression of oncogenic ETS and upregulation of tumor-suppressive GATA programs.

2018-05-01 | GSE86490 | GEO

UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs

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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

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.

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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

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

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

2016-03-22 | GSE69968 | GEO

RNA-seq data of mouse cerebral cortex in control and UTX conditional knockout groups

Project description:We demonstrate that UTX deficiency increases neural progenitor cells (NPCs) proliferation, decreases terminal mitosis and neuronal differentiation. Furthermore, we discover that impairment of cortex development caused by lack of UTX is less significant in males than in females. And further knockdown of UTY in male UTX-deficient cortex makes the phenotype consistent with the female’s. In order to understand the amount of gene expression, gene expression differences, as well as differences in gene patterns and functional clustering and other aspects of the situation after UTX conditional knockout in cortex, we conducted RNA-seq.

2018-02-10 | GSE110392 | GEO

Transcription profiling of human cancers with inactivating somatic mutations of the histone H3K27 demethylase UTX

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.

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