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Project description:Ezh2 epigenetically suppresses developmentally-regulated genes. Ezh2 is highly expressed during development, including in the lung. We knocked out Ezh2 in the developing lung epithelium using a Shh-cre driver which is active in foregut endoderm prior to lung morphogenesis. Many developmentally regulated genes became derepressed in the mutant lungs, leading to defects in lung development. Microarray analysis of genes upregulated in Ezh2 epithelial knock-out mouse lungs compared to Shh-cre controls. We generated Ezh2 epithelial mutant lungs by crossing the Ezh2-floxed line (Su et al., 2003) with the Shh-cre line (Harfe et al., 2004). We isolated RNA from whole mouse lungs at embryonic day 14.5 from 4 Shh-cre:Ezh2-flox/flox embryos (M1-M4) and 4 Shh-cre embryos (C1-C4). Littermates are as follows: C1+C2; C3+C4; M1+M2; M3+M4.
2015-02-04 | E-GEOD-60660 | biostudies-arrayexpress
Project description:Chromatin immunoprecipitation and sequencing for 3 histone marks (H3K27ac, H3K27me3 and H3K4me1) was performed on livers of male and female mice with a combined loss of Ezh1 and Ezh2. The DKO mouse model used in these analyses is a global deletion of Ezh1 and hepatocyte-specific deletion of Ezh2, and is described in Bae WK et al, FASEB J. 2015 May;29(5):1653-62. doi: 10.1096/fj.14-261537. PMID: 25477280.
2020-04-28 | GSE110887 | GEO
Project description:The responses of macrophages to lipopolysaccharide (LPS) might determine the direction of clinical manifestations of sepsis, which is the immune response against severe infection. Meanwhile, the enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase of epigenetic regulation, might interfere with LPS response. With a single LPS stimulation, Ezh2 null(Ezh2flox/flox; LysM-Crecre/−) macrophages demonstrated lower supernatant TNF-α than Ezh2 control (Ezh2fl/fl; LysM-Cre−/−), perhaps due to an upregulation of Socs3, which is a suppressor of cytokine signaling 3, due to the loss of the Ezh2 gene. In LPS tolerance, Ezh2 null macrophages indicated higher supernatant TNF-α and IL-6 than the control, supporting an impact of the loss of the Ezh2 inhibitory gene. In parallel, Ezh2 null mice demonstrated lower serum TNF-α and IL-6 than the control mice after an LPS injection, indicating a less severe LPS-induced hyper-inflammation in Ezh2 null mice. In conclusion, an absence of Ezh2 in macrophages resulted in less severe LPS-induced inflammation, as indicated by low serum cytokines, with less severe LPS tolerance, as demonstrated by higher cytokine production, partly through the upregulated Socs3.
2023-07-20 | PXD041265 | Pride
Project description:RNAs directly interacting with EZH2 were isolated from human colorectal HCT116 cells using an in vivo crosslinking and immunoprecipitation strategy (iCLIP, König J et al, Nat Struct Mol Biol 2010) coupled to an ultrasequencing approach.
2012-04-23 | GSE36070 | GEO
Project description:We studied transcriptional changes by Affymetrix human microarrays in DLBCL cell lines as a result of treatment with GSK126, a potent, highly-selective, SAM-competitive, small molecule inhibitor of EZH2 In eukaryotes, epigenetic post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and is responsible for repressing target gene expression through methylation of histone H3 on lysine 27 (H3K27). Over-expression of EZH2 is implicated in tumorigenesis and correlates with poor prognosis in multiple tumor types. Recent reports have identified somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The Y641 residue is the most frequently mutated residue, with 22% of GCB (Germinal Cell B-cell) DLBCL and FL harboring mutations at this site. These lymphomas exhibit increased H3K27 tri-methylation (H3K27me3) due to altered substrate preferences of the mutant enzymes. However, it is unknown whether direct inhibition of EZH2 methyltransferase activity alone will be effective in treating lymphomas carrying activating EZH2 mutations. Herein, we demonstrate that GSK126, a potent, highly-selective, SAM-competitive, small molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and dramatically inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma. 10 DLBCL cell lines (7 mutant and 3 wild type EZH2), that were differentially sensitive to GSK126 in proliferation assays, were treated for 72 hours, in duplicate (n=2), with either DMSO (vehicle) or 500nM of GSK126, a potent selective EZH2 inhibitor. EZH2 mutant cell lines are Pfeiffer, KARPAS-422, WSU-DLCL2, SU-DHL-10, SU-DHL-6, DB and SU-DHL-4. EZH2 wildtype cell lines are HT, OCI-LY-19 and Toledo.
2012-10-12 | E-GEOD-40971 | biostudies-arrayexpress
Project description:Loss-of-function mutations in EZH2 are associated with worse outcomes in patients with primary myelofibrosis (PMF). To understand how EZH2 insufficiency is involved in the pathogenesis of PMF, we generated mice compound for Ezh2 conditional deletion and a JAK2V617F transgene. The total bone marrow cells isolated from Cre-ERT2, Ezh2flox/flox;Cre-ERT2, JAK2V617F;Cre-ERT2 and JAK2V617F;Ezh2flox/flox;Cre-ERT2 mice were transplanted into lethally irradiated CD45.1+ wild-type recipient mice. As we deleted Ezh2 at four weeks post transplantation, we performed gene-expression analysis of LSKs and MEPs isolated from the recipient mice at 2 months post transplantation.
2015-06-04 | E-GEOD-69498 | biostudies-arrayexpress
Project description:This experiment was designed to indentify RNAs making direct contact with EZH2 in mouse embryonic stem cells E14 with an integrated transgene encoding HA-EZH2 were pulsed with 4-SU, irradiated with UV, and subjected to HA immunoprecipitation.
2013-10-19 | E-GEOD-49433 | biostudies-arrayexpress
Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.
2018-07-03 | PXD010073 | Pride
Project description:RNAs directly interacting with EZH2 were isolated from human colorectal HCT116 cells using an in vivo crosslinking and immunoprecipitation strategy (iCLIP, König J et al, Nat Struct Mol Biol 2010) coupled to an ultrasequencing approach. RIP sequencing for 1 Human sample
2012-04-23 | E-GEOD-36070 | biostudies-arrayexpress