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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Mdm2 enhances stemness-promoting chromatin modifications through the Polycomb Repressor Complex 2 in a p53-Independent Manner [RNA-Seq]

ABSTRACT: The Mdm2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that Mdm2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, Mdm2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the Mdm2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. Mdm2 physically associated with EZH2 on chromatin, enhancing the trimethylation of Histone 3 at lysine 27 and the ubiquitination of Histone 2A at lysine 119 (H2AK119) at its target genes. Removing Mdm2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, Mdm2 supports the Polycomb-mediated repression of lineage specific genes independent of p53. Expression profiling by high throughput sequencing of p53 ko MEFs, p53Mdm2 ko MEFs, p53ko Mdm2 C462A ki MEFs.

ORGANISM(S): Mus musculus

SUBMITTER: Magdalena Wienken

PROVIDER: E-GEOD-73176 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Mdm2 enhances stemness-promoting chromatin modifications through the Polycomb Repressor Complex 2 in a p53-Independent Manner [HCT116 microarray]

Project description:The Mdm2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that Mdm2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, Mdm2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the Mdm2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. Mdm2 physically associated with EZH2 on chromatin, enhancing the trimethylation of Histone 3 at lysine 27 and the ubiquitination of Histone 2A at lysine 119 (H2AK119) at its target genes. Removing Mdm2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, Mdm2 supports the Polycomb-mediated repression of lineage specific genes independent of p53. microarray analysis in HCT116 p53-/-cells

2015-12-31 | E-GEOD-73294 | biostudies-arrayexpress

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Mdm2 enhances stemness-promoting chromatin modifications through the Polycomb Repressor Complex 2 in a p53-Independent Manner [ChIP-Seq]

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Mdm2 enhances stemness-promoting chromatin modifications through the Polycomb Repressor Complex 2 in a p53-Independent Manner [HCT116 microarray]

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Mdm2 enhances stemness-promoting chromatin modifications through the Polycomb Repressor Complex 2 in a p53-Independent Manner [ChIP-Seq]

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Mdm2 enhances stemness-promoting chromatin modifications through the Polycomb Repressor Complex 2 in a p53-Independent Manner [RNA-Seq]

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Epigenetic antagonism between Snf5 and Ezh2 during oncogenic transformation

Project description:Epigenetic alterations have been increasingly implicated in oncogenesis. Analysis of Drosophila mutants suggests that Polycomb and SWI/SNF complexes can serve antagonistic developmental roles. However, the relevance of this relationship to human disease is unclear. Here we have investigated functional relationships between these epigenetic regulators in oncogenic transformation. Mechanistically, we show that loss of the SNF5 tumor suppressor leads to elevated expression of the Polycomb gene EZH2 and that Polycomb targets are broadly H3K27-trimethylated and repressed in SNF5-deficient fibroblasts and cancers. Further, we show antagonism between SNF5 and EZH2 in the regulation of stem cell-associated programs and that Snf5 loss activates those programs. Finally, using conditional mouse models, we show that inactivation of Ezh2 blocks tumor formation driven by Snf5 loss. Mouse Embryonic Fibroblasts (MEFs) conditionally inactivated for Ezh2, Snf5 and Ezh2, or from control WT MEFs were used to evaluated epigenetic antagonism between Snf5 and Ezh2 in the control of gene expression programs. Snf5-deficient lymphoma samples and control CD8+ WT T-cells were used to evaluate genetic programs misregulated by Snf5 inactivation during tumorigenesis. RNA was isolated from each of these samples and used for gene expression profiling on Affymetrix arrays.

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ChipSeq of conditional knock-in mouse carrying the R178E (EE) mutation in exon 5 of the endogenous mouse Trp53 gene locus.

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2019-09-03 | E-MTAB-6793 | biostudies-arrayexpress

Nanostring microRNA microarry analysis of p53 and Mdm2 knockout mouse hearts compared to vehicle-injected negative controls

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2017-03-22 | E-MTAB-5531 | biostudies-arrayexpress

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