UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE103567 | GEO | 2017/10/25
SECONDARY ACCESSION(S): PRJNA401933
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.
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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.
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Project description:Loss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion, and tumorigenicity of MM cells. Moreover, UTX mutant cells showed increased in vitro and in vivo sensitivity to inhibition of EZH2, a histone methyltransferase that generates H3K27me3. Such sensitivity was related to a decrease in the levels of IRF4 and c-MYC and an activation of repressors of IRF4 characteristic of germinal center B cells such as BCL6 and IRF1. Rebalance of H3K27me3 levels at specific genes through EZH2 inhibitors may be a therapeutic strategy in MM cases harboring UTX mutations.
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Project description:UTX/KDM6A is known to promote open chromatin structure to facilitate gene activation. Although UTX is important for normal and cancer development, its molecular activities in developmental gene regulation remain unclear. Using genetic knockout of UTX in human embryonic stem cells, we show that UTX promotes human pluripotency and suppresses neural differentiation. In human neural stem cells (hNSCs), UTX modulates self-renewal, is required for neuronal differentiation, and suppresses glial/astrocytic differentiation by positively and negatively regulating its target genes. 70% of UTX-occupied regions are associated with epigenetic modifications known to be influenced by UTX, and UTX knockout leads to significant changes in expression of more than 50% of its target genes but epigenetic changes in less than 6% of its target genes. UTX likely affects gene expression via alternative molecular activities in hNSCs. Our findings reveal new functions of UTX in gene regulation and cell fate decisions in human stem cells.
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Project description:UTX/KDM6A is known to promote open chromatin structure to facilitate gene activation. Although UTX is important for normal and cancer development, its molecular activities in developmental gene regulation remain unclear. Using genetic knockout of UTX in human embryonic stem cells, we show that UTX promotes human pluripotency and suppresses neural differentiation. In human neural stem cells (hNSCs), UTX modulates self-renewal, is required for neuronal differentiation, and suppresses glial/astrocytic differentiation by positively and negatively regulating its target genes. 70% of UTX-occupied regions are associated with epigenetic modifications known to be influenced by UTX, and UTX knockout leads to significant changes in expression of more than 50% of its target genes but epigenetic changes in less than 6% of its target genes. UTX likely affects gene expression via alternative molecular activities in hNSCs. Our findings reveal new functions of UTX in gene regulation and cell fate decisions in human stem cells.
2020-11-17 | GSE127512 | GEO
Project description:UTX/KDM6A is known to promote open chromatin structure to facilitate gene activation. Although UTX is important for normal and cancer development, its molecular activities in developmental gene regulation remain unclear. Using genetic knockout of UTX in human embryonic stem cells, we show that UTX promotes human pluripotency and suppresses neural differentiation. In human neural stem cells (hNSCs), UTX modulates self-renewal, is required for neuronal differentiation, and suppresses glial/astrocytic differentiation by positively and negatively regulating its target genes. 70% of UTX-occupied regions are associated with epigenetic modifications known to be influenced by UTX, and UTX knockout leads to significant changes in expression of more than 50% of its target genes but epigenetic changes in less than 6% of its target genes. UTX likely affects gene expression via alternative molecular activities in hNSCs. Our findings reveal new functions of UTX in gene regulation and cell fate decisions in human stem cells.
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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.
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Project description:UTX gene is localized on the X chromosome, identified as a demethylase on histone H3 lysine 27. Two independent UTX conditional knockout (cKO) embryonic stem cell lines and two UTX knockout (KO) cell lines were cultured on 0.1% gelatin-coated dishes without feeder cells at desity of 1 million cells/10 cm dish. Cells were cultured overnight and collected. Total RNAs were sequentially purified with Trizol (Invitrogen) and RNeasy kit (Qiagen) and analyzed on Mouse Genome 430 2.0 Array (Affymetrix) at NIDDK Microarray Core Facility following standard protocols.
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