KDM6A(UTX) is an epigenetic gatekeeper of mTORC1 signalling in cancer
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ABSTRACT:
PROVIDER: PRJNA650533 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12376950_1.fastq.gz | Fastqsanger.gz | |||
| SRR12376950_2.fastq.gz | Fastqsanger.gz | |||
| SRR12376951_1.fastq.gz | Fastqsanger.gz | |||
| SRR12376951_2.fastq.gz | Fastqsanger.gz | |||
| SRR12376952_1.fastq.gz | Fastqsanger.gz |
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Project description:Large-scale genome sequencing efforts of human tumors identified epigenetic modifiers as one of the most frequently mutated gene class in human cancer. However, how these mutations drive tumor development and progression is largely unknown. Here, we identify the histone demethylase KDM6A as an important tumor suppressor in solid cancers, such as liver cancer and pancreatic cancer. KDM6A-deficient tumors show hyperactivation of mTORC1 signaling, whereas endogenous KDM6A re-expression in established KDM6A-deficient tumors diminishes mTORC1 activity by fostering the expression of crucial negative pathway regulators, such as DEPTOR, TSC1, and TSC2, resulting in tumor regression. Importantly, KDM6A expression in human tumors correlates with mTORC1 activity and KDM6A-deficient tumors exhibit increased sensitivity to mTORC1 inhibition. Hence, our results link KDM6A-dependent epigenetic remodeling to mTORC1 signaling and provide a potential therapeutic strategy for KDM6A-deficient tumors.
2022-07-20 | GSE155630 | GEO
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
Project description:ObjectiveLarge-scale genome sequencing efforts of human tumours identified epigenetic modifiers as one of the most frequently mutated gene class in human cancer. However, how these mutations drive tumour development and tumour progression are largely unknown. Here, we investigated the function of the histone demethylase KDM6A in gastrointestinal cancers, such as liver cancer and pancreatic cancer.DesignGenetic alterations as well as expression analyses of KDM6A were performed in patients with liver cancer. Genetic mouse models of liver and pancreatic cancer coupled with Kdm6a-deficiency were investigated, transcriptomic and epigenetic profiling was performed, and in vivo and in vitro drug treatments were conducted.ResultsKDM6A expression was lost in 30% of patients with liver cancer. Kdm6a deletion significantly accelerated tumour development in murine liver and pancreatic cancer models. Kdm6a-deficient tumours showed hyperactivation of mTORC1 signalling, whereas endogenous Kdm6a re-expression by inducible RNA-interference in established Kdm6a-deficient tumours diminished mTORC1 activity resulting in attenuated tumour progression. Genome-wide transcriptional and epigenetic profiling revealed direct binding of Kdm6a to crucial negative regulators of mTORC1, such as Deptor, and subsequent transcriptional activation by epigenetic remodelling. Moreover, in vitro and in vivo genetic epistasis experiments illustrated a crucial function of Deptor and mTORC1 in Kdm6a-dependent tumour suppression. Importantly, KDM6A expression in human tumours correlates with mTORC1 activity and KDM6A-deficient tumours exhibit increased sensitivity to mTORC1 inhibition.ConclusionKDM6A is an important tumour suppressor in gastrointestinal cancers and acts as an epigenetic toggle for mTORC1 signalling. Patients with KDM6A-deficient tumours could benefit of targeted therapy focusing on mTORC1 inhibition.
| S-EPMC9279849 | biostudies-literature
Project description:Using a CRISPR-based autochthonous SCLC GEMM to study the consequences of KDM6A/UTX inactivation, we found that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumors with open chromatin at the NEUROD1 promoter that express both ASCL1 and NEUROD1. Mechanistically, KDM6A binds and maintains ASCL1 target genes in an active chromatin state with its loss increasing H3K27me3 near their promoters leading to a cell state that is primed for ASCL1 to NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides a novel autochthonous SCLC GEMM to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.
2023-06-09 | GSE211160 | GEO
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
Project description:Using a CRISPR-based autochthonous SCLC GEMM to study the consequences of KDM6A/UTX inactivation, we found that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumors with open chromatin at the NEUROD1 promoter that express both ASCL1 and NEUROD1. Mechanistically, KDM6A binds and maintains ASCL1 target genes in an active chromatin state with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1 to NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides a novel autochthonous SCLC GEMM to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.
2023-06-09 | GSE228345 | GEO
Project description:Paternal chromatin undergoes extensive structural and epigenetic changes during mammalian spermatogenesis, producing sperm with an epigenome optimized for the transition to embryogenesis. Lysine demethylase 6a (KDM6A, also called UTX) promotes gene activation in part via demethylation of H3K27me3, a developmentally important repressive modification abundant throughout the epigenome of spermatogenic cells and sperm. We previously demonstrated increased cancer risk in genetically wild type mice derived from a paternal germ line lacking Kdm6a (Kdm6a cKO), indicating a role for KDM6A in regulating heritable epigenetic states. However, the regulatory function of KDM6A during spermatogenesis is not known. Here, we show that Kdm6a is transiently expressed in spermatogenesis, with RNA and protein expression largely limited to late spermatogonia and early meiotic prophase. Kdm6a cKO males do not have defects in fertility or the overall progression of spermatogenesis. However, hundreds of genes are deregulated upon loss of Kdm6a in spermatogenic cells, with a strong bias towards downregulation coinciding with the time when Kdm6a is expressed. Misregulated genes encode factors involved in chromatin organization and regulation of repetitive elements, and a subset of these genes was persistently deregulated in the male germ line across two generations of offspring of Kdm6a cKO males. Genome-wide epigenetic profiling revealed broadening of H3K27me3 peaks in differentiating spermatogonia of Kdm6a cKO mice, suggesting that KDM6A demarcates H3K27me3 domains in the male germ line. Our findings highlight KDM6A as a transcriptional activator in the mammalian male germ line that is dispensable for spermatogenesis but important for safeguarding gene regulatory state intergenerationally.
2023-10-24 | GSE215112 | 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.
2020-11-17 | GSE127514 | 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.
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.
2020-11-17 | GSE127511 | GEO