Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target [Affymetrix]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE69251 | GEO | 2015/12/31
SECONDARY ACCESSION(S): PRJNA285036
REPOSITORIES: GEO
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Project description:in this study we define an epigenomic profile of PRC2 (H3K27me3 and bivalent) tragets in four newly diagnosed MM patients. Using Oncomine database we demonstarte that PRC2 targets are underexpressed with advanced ISS stages and correlated to poor outcome. Pharmacological inhibition of UNC1999 showed anti-myeloma potential in vitro by activating the expression genes related to apoptosis and cell differenatiation. In this array the differences between the gene expression profiles of samll molecule inhibitor (UNC1999) of EZH2 and the control (UNC2400) have been tested. So multiple myeloma cell line INA-6 was treated with 2μM of UNC1999 and UNC2400. This design contains three biological replicates.
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Project description:Ezh2 and EZH1 are histone H3 lysine 27 specific methyltransferase. Their hyperactive mutations and overexpression were found in cancer including various hematological malignancies. UNC1999 is a highly selective inhibitor for both enzymes. It suppresses H3K27 tri- and di-methylation globally and inhibits growth of MLL-rearranged acute leukemia cell lines. UNC2400, a di-methylated derivative of UNC1999, is employed an inactive analog compound for assessment of off-target effects. EED knockdown was used to demonstrate gene targets of PRC2. Here we performed microarray analysis in MLL-AF9 transformed acute leukemia cells following treatment with DMSO, UNC2400 or UNC1999, or after induction of EED shRNA (Renilla shRNA as control). This study allows us to identify UNC1999-responsive gene signatures as well as their overlap with PRC2 targets in MLL-AF9-bearing leukemia cells. We analyzed 5 of DMSO-treated, 5 of UNC2400 (inactive analog of UN1999)-treated, and 6 of UNC1999-treated MLL-AF9 leukemia cell samples to identify UNC1999-responsive gene signatures. We also performed microarray in 3 of shRNA control lines (Renilla or Ren) and 3 of shEED lines to identify downstream targets of PRC2 complex in MLL-AF9 leukemia cells.
2014-10-10 | E-GEOD-62198 | biostudies-arrayexpress
Project description:Ezh2 and EZH1 are histone H3 lysine 27 specific methyltransferase. Their hyperactive mutations and overexpression were found in cancer including various hematological malignancies. UNC1999 is a highly selective inhibitor for both enzymes. It suppresses H3K27 tri- and di-methylation globally and inhibits growth of MLL-rearranged acute leukemia cell lines. UNC2400, a di-methylated derivative of UNC1999, is employed an inactive analog compound for assessment of off-target effects. EED knockdown was used to demonstrate gene targets of PRC2. Here we performed microarray analysis in MLL-AF9 transformed acute leukemia cells following treatment with DMSO, UNC2400 or UNC1999, or after induction of EED shRNA (Renilla shRNA as control). This study allows us to identify UNC1999-responsive gene signatures as well as their overlap with PRC2 targets in MLL-AF9-bearing leukemia cells.
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Project description:Differentiation of naïve CD4+ T cells into effector (Th1, Th2 and Th17) and induced regulatory (iTreg) T cells requires lineage-specifying transcription factors and epigenetic modifications that allow appropriate repression or activation of gene transcription. The epigenetic silencing of cytokine genes is associated with the repressive H3K27 trimethylation mark, mediated by Ezh2 or Ezh1 methyltransferase components of the polycomb repressive complex 2 (PRC2). EZH2 over-expression and activating mutations are implicated in tumorigenesis and correlate with poor prognosis in several tumor types 35. This spurred the development of EZH2 inhibitors which, by inducing tumor cell growth arrest and cell death, show therapeutic promise in cancer. A role for Ezh2 in suppressing Th1 and Th2 cytokine production and survival has recently been reported. It is not entirely clear whether Ezh2-PRC2 plays a role in H3K27me3 in cytokine loci in naïve CD4+ T cells and whether H3K27me3 has a non-redundant role in T helper cell lineage differentiation and survival. Here, we investigate the effects of T cell-specific Ezh2 deletion to determine the role that Ezh2-PRC2 plays in regulating the fate of differentiating naïve CD4+ T cells. Loss of Ezh2 altered the expression of 1328 genes in Th0 and 1979 genes in iTreg cells. Gene expression changes were positively correlated in both cell types, indicating that Ezh2 targets similar genes in these cells. As expected, Ifng was one of the genes most increased in expression by following loss of Ezh2. In addition, expression of Tbx21 homolog Eomes, a transcription factor that regulates IFNG production, was also significantly increased. We then performed H3K27me3 ChIP-seq on Ezh2fl/fl and Ezh2fl/fl.CD4Cre Th0 cells. Consistent with cellular phenotype and RNA-seq data, we observed a loss of the H3K27me3 at Eomes, Il4 and Il10 loci . Very low levels of H3K27me3 marks were present at Ifng and Tbx21 loci in differentiated Ezh2fl/fl Th0 cells, suggesting that upon differentiation, upregulation or activation of transcription factors accounts for IFNG overproduction. A significant loss of H3K27me3 was observed >2kb upstream of Gata3 locus , however this did not result in increased transcription . Of the 22381 genes tested for changes in H3K27me3, 1360 showed a statistically significant decrease in Ezh2fl/fl.CD4Cre Th0 cells, compared to wildtype. Furthermore, 404 of these genes also showed a concomitant gain in expression in Ezh2fl/fl.CD4Cre Th0 cells, suggesting that these loci are likely direct Ezh2-PRC2 targets. There are 3 biological replicates each of Ezh2fl/fl.CD4Cre and Ezh2fl/fl in both Th0 and iTreg cells for the RNA-seq experiment. There are 2 biological replicates each of Ezh2fl/fl.CD4Cre and Ezh2fl/fl in Th0 cells for the ChIP-seq experiment.
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Project description:In this study, we investigated PRC2 (polycomb repressive complex 2), the H3K27me3 modifier, in naive hES cells for its roles in regulating 8-cell (8C) stage genes expression. EZH2 inhibitor, UNC1999 and its inactive analog UNC2400 were used for the treatment.
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Project description:Differentiation of naïve CD4+ T cells into effector (Th1, Th2 and Th17) and induced regulatory (iTreg) T cells requires lineage-specifying transcription factors and epigenetic modifications that allow appropriate repression or activation of gene transcription. The epigenetic silencing of cytokine genes is associated with the repressive H3K27 trimethylation mark, mediated by Ezh2 or Ezh1 methyltransferase components of the polycomb repressive complex 2 (PRC2). EZH2 over-expression and activating mutations are implicated in tumorigenesis and correlate with poor prognosis in several tumor types 35. This spurred the development of EZH2 inhibitors which, by inducing tumor cell growth arrest and cell death, show therapeutic promise in cancer. A role for Ezh2 in suppressing Th1 and Th2 cytokine production and survival has recently been reported. It is not entirely clear whether Ezh2-PRC2 plays a role in H3K27me3 in cytokine loci in naïve CD4+ T cells and whether H3K27me3 has a non-redundant role in T helper cell lineage differentiation and survival. Here, we investigate the effects of T cell-specific Ezh2 deletion to determine the role that Ezh2-PRC2 plays in regulating the fate of differentiating naïve CD4+ T cells. Loss of Ezh2 altered the expression of 1328 genes in Th0 and 1979 genes in iTreg cells. Gene expression changes were positively correlated in both cell types, indicating that Ezh2 targets similar genes in these cells. As expected, Ifng was one of the genes most increased in expression by following loss of Ezh2. In addition, expression of Tbx21 homolog Eomes, a transcription factor that regulates IFNG production, was also significantly increased. We then performed H3K27me3 ChIP-seq on Ezh2fl/fl and Ezh2fl/fl.CD4Cre Th0 cells. Consistent with cellular phenotype and RNA-seq data, we observed a loss of the H3K27me3 at Eomes, Il4 and Il10 loci . Very low levels of H3K27me3 marks were present at Ifng and Tbx21 loci in differentiated Ezh2fl/fl Th0 cells, suggesting that upon differentiation, upregulation or activation of transcription factors accounts for IFNG overproduction. A significant loss of H3K27me3 was observed >2kb upstream of Gata3 locus , however this did not result in increased transcription . Of the 22381 genes tested for changes in H3K27me3, 1360 showed a statistically significant decrease in Ezh2fl/fl.CD4Cre Th0 cells, compared to wildtype. Furthermore, 404 of these genes also showed a concomitant gain in expression in Ezh2fl/fl.CD4Cre Th0 cells, suggesting that these loci are likely direct Ezh2-PRC2 targets.
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Project description:Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.
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