The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA611997 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11290100.fastq.gz | Fastqsanger.gz | |||
| SRR11290101.fastq.gz | Fastqsanger.gz | |||
| SRR11290102.fastq.gz | Fastqsanger.gz | |||
| SRR11290103.fastq.gz | Fastqsanger.gz | |||
| SRR11290104.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 37 |
Similar Datasets
Project description:Pluripotent cells of the mammalian embryo undergo extensive chromatin rewiring to prepare for lineage commitment after implantation. Repressive H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), is reallocated from large blankets in pre-implantation embryos to mark promoters of developmental genes. The regulation of the global redistribution of H3K27me3 is poorly understood. Here we report a post-translational mechanism that destabilizes PRC2 to constrict H3K27me3 during lineage commitment. Using an auxin-inducible degron system, we show that the deubiquitinase Usp9x is required for mouse embryonic stem (ES) cell self-renewal. Usp9x-high ES cells have high PRC2 levels and bear a chromatin and transcriptional signature of the pre-implantation embryo, whereas Usp9x-low ES cells resemble the post-implantation, gastrulating epiblast. We show that Usp9x interacts with, deubiquitinates and stabilizes PRC2. Deletion of Usp9x in post-implantation embryos results in the derepression of genes that normally gain H3K27me3 after gastrulation, followed by the appearance of morphological abnormalities at E9.5, pointing to a recurrent link between Usp9x and PRC2 during development. Usp9x is a marker of “stemness” and is mutated in various neurological disorders and cancers. Our results unveil a Usp9x-PRC2 regulatory axis that is critical at peri-implantation and may be redeployed in other stem cell fate transitions and disease states.
2021-01-25 | GSE146800 | GEO
Project description:Pluripotent cells of the mammalian embryo undergo extensive chromatin rewiring to prepare for lineage commitment after implantation. Repressive H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), is reallocated from large blankets in pre-implantation embryos to mark promoters of developmental genes. The regulation of this global redistribution of H3K27me3 is poorly understood. Here we report a post-translational mechanism that destabilizes PRC2 to constrict H3K27me3 during lineage commitment. Using an auxin-inducible degron system, we show that the deubiquitinase Usp9x is required for mouse embryonic stem (ES) cell self-renewal. Usp9x-high ES cells have high PRC2 levels and bear a chromatin and transcriptional signature of the pre-implantation embryo, whereas Usp9x-low ES cells resemble the post-implantation, gastrulating epiblast. We show that Usp9x interacts with, deubiquitinates and stabilizes PRC2. Deletion of Usp9x in post-implantation embryos results in the derepression of genes that normally gain H3K27me3 after gastrulation, followed by the appearance of morphological abnormalities at E9.5, pointing to a recurrent link between Usp9x and PRC2 during development. Usp9x is a marker of "stemness" and is mutated in various neurological disorders and cancers. Our results unveil a Usp9x-PRC2 regulatory axis that is critical at peri-implantation and may be redeployed in other stem cell fate transitions and disease states.
| S-EPMC7994559 | biostudies-literature
Project description:Ewing’s sarcoma (EWS) is a cancer of the bones or soft tissues in children and adolescents. EWS-FLI1 is a transcriptional factor and the key driver of EWS. To characterize the changes of downstream transcriptional profiles of EWS-FLI1 in A673 cells upon knockdown of EWS-FLI1 and deubiquitinase USP9X, RNA-seq was performed in A673 cells transfected with EWS-FLI1 esiRNA, USP9X esiRNA or GFP esiRNA as control. The data indicates that USP9X regulates transcriptional profiles of EWS through mediating EWS-FLI1.
2022-01-01 | GSE185429 | GEO
Project description:mTOR is a central regulator of mammalian metabolism and physiology. Aberrant hyperactivation of this pathway promotes tumor growth and metastasis and drives tumor resistance to chemotherapy and cancer drugs, making mTOR an attractive cancer therapeutic target. mTOR inhibitors have been approved to treat cancer, however, the basis for drug sensitivity remains poorly understood. Here, whole exome sequencing of three chromophobe renal cell carcinoma (chRCC) patients with exceptional mTOR inhibitor sensitivity, uncovered USP9X deubiquitinase as the only mutated gene shared by the tumors. The clonal characteristics of the mutations, revealed by studying multiple patients’ primary and metastatic samples along the years, together with the low USP9X mutation rate in unselected chRCC series, reinforced a causal link between USP9X and mTOR inhibitor sensitivity. Rapamycin treatment of USP9X depleted HeLa and renal cancer 786-O cells and the pharmacological inhibition of USP9X, confirmed a crucial role of this protein in the patients’ sensitivity to mTOR inhibition. As no direct effect of USP9X in mTORC1 was detected, we performed ubiquitylome analyses that identified p62 as a direct USP9X target. Increased p62 ubiquitination and an augmented rapamycin effect upon bortezomib treatment, together with p62 and LC3 immunofluorescence assays, suggested that dysregulated autophagy in USP9X depleted cells can synergize with mTOR inhibitors. In summary, here we show that USP9X constitutes a potential novel marker of sensitivity to mTOR inhibitors in chRCC patients and represents a clinically exploitable strategy that could increase sensitivity to these drugs
2023-06-14 | PXD040496 | Pride
Project description:Radioresistance is regarded as the main barrier to effective radiotherapy in lung cancer. However, the underlying mechanisms of radioresistance remain elusive. Here, we show that lysine-specific demethylase 4C (KDM4C) is overexpressed and correlated with poor prognosis in lung cancer patients. We provide evidence that genetical or pharmacological inhibition of KDM4C impairs tumorigenesis and radioresistance in lung cancer in vitro and in vivo. Moreover, we uncover that KDM4C upregulates TGFβ2 expression by directly reducing H3K9me3 level at the TGFβ2 promoter and then activates TGF-β/Smad/ATM signaling to confer radioresistance in lung cancer. Using tandem affinity purification technology, we further identify deubiquitinase USP9X as a critical binding partner which deubiquitinates and stabilizes KDM4C. More importantly, depletion of USP9X impairs TGF-β/Smad signaling and radioresistance by destabilizing KDM4C in lung cancer cells. Thus, our findings demonstrate that USP9X-mediated KDM4C deubiquitination activates TGF-β/Smad signaling to promote radioresistance, suggesting that targeting KDM4C may be a promising radiosensitization strategy in the treatment of lung cancer.
2021-07-14 | GSE136404 | GEO
Project description:Correct neural progenitor fate determination requires the coordination of extrinsic fate determinant signals with intrinsic responses. Post-translational modifications dynamically alter protein function and so are ideally situated to regulate development. Here we show that the deubiquitylaying enzyme, Usp9x modulates both intrinsic and extrinsic regulators of mouse neural progenitors. Nestin-cre mediated deletion of Usp9x from neural progenitors results in a transient disruption of cell adhesion and apical-basal polarity as well as the premature differentiation of intermediate neural progenitors. Ablation of Usp9x also significantly increased β-catenin protein levels, especially S33/S37/T41 phospho-β-catenin, and Wnt signalling. Usp9x was found to be part of the β-catenin destruction complex and loss of Usp9x affects destruction complex composition. Notch signalling was also increased in Usp9x ablated neural progenitors, coinciding with decreased Itch and Numb, and increased Notch intracellular domain protein levels. Usp9x co-localized and immunopreciptiated with Numb from neural progenitors suggesting it is required for Numb stabilisation. These data suggest Usp9x plays a role in coordinating intrinsic responses to extrinsic signals during neural development.
2017-08-18 | E-MTAB-4150 | biostudies-arrayexpress
Project description:Assay the ubiquitinated protein remmants post depletion or inhibition of the deubiquitinase Usp9x in melanoma cells.
2017-02-20 | PXD005417 | Pride
Project description:The deubiquitinase USP9X related with multiple diseases including neurodegeneration, epilepsy and various type of tumor, by targeting different substrates. In our study, to deep study USP9X functional candidate substrates, we performed SILAC-based quantitative proteomic to compare knockdown USP9X with wild type HeLa cells to screen USP9X potential substrates. Further, we carried out Flag-NFX1-123 affinity tag-based interaction mass spectrometry method and verified that the X-box binding nuclear factor NFX1-123 is a substrate of USP9X. Further experimental evidences confirmed that USP9X stabilizedNFX1-123 protein level rather than mRNA levels via direct interaction and efficient deubiquitination of NFX1-123 protein
2019-05-13 | PXD012871 | Pride
Project description:The X-linked deubiquitinase, USP9X, is implicated in multiple cancers by targeting various substrates. Increased expression of USP9X is observed in non-small cell lung cancer (NSCLC) and is correlated with poor prognosis. However, the molecular mechanism for USP9X regulating tumor cell survival and tumorigenesis in NSCLC is less defined. In this study, chemical labeling quantitative proteomic screening was applied to analyze A549 cells with or without USP9X RNA interference, and the resulting data suggested that TTK is a potential substrate of USP9X. Further experimental evidences confirmed that USP9X stabilized TTK via direct interaction and deubiquitination of TTK. Moreover, knockdown of USP9X or TTK inhibited cell proliferation, migration and tumorigenesis, and the immunohistochemical analysis of clinical NSCLC samples showed that the protein expression levels of USP9X and TTK were significantly elevated and positively correlated in tumor tissues. In summary, our data demonstrated that the USP9X-TTK axis may play a critical role in NSCLC, and could be considered as the potential therapeutic target.
2018-05-07 | PXD007726 | Pride
Project description:The tumor suppressor FBW7 targets oncoproteins such as c-MYC for ubiquitylation and is mutated in several human cancers. We noted that in a substantial percentage of colon cancers, FBW7 protein is undetectable despite the presence of FBW7 mRNA. To understand the molecular mechanism of FBW7 regulation in these cancers, we employed proteomics and identified the deubiquitinase (DUB) USP9X as an FBW7 interactor. USP9X antagonized FBW7 ubiquitylation, and Usp9x deletion caused Fbw7 destabilization. Mice lacking Usp9x in the gut showed reduced secretory cell differentiation and increased progenitor proliferation, phenocopying Fbw7 loss. In addition, Usp9x inactivation impaired intestinal regeneration and increased tumor burden in colitis-associated intestinal cancer. c-Myc heterozygosity abrogated increased progenitor proliferation and tumor burden in Usp9x-deficient mice, suggesting that Usp9x suppresses tumor formation by regulating Fbw7 protein stability and thereby reducing c-Myc. Thus, we identify a tumor suppressor mechanism in the mammalian intestine that arises from the posttranslational regulation of FBW7 by USP9X independent of somatic FBW7 mutations.
| S-EPMC5873885 | biostudies-literature