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GSE17140
Mus musculus
6 Downloadable Samples
Affymetrix Mouse Expression 430A Array (moe430a)
Description
Objective of this study was to find changes in gene expression of mouse multiple myeloma cells upon treatment with IGF-1
Publication Title
IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms.
Sample Metadata Fields
Specimen part, Disease, Disease stage
View Samples- Mus musculus
- 16 Downloadable Samples
Illumina HiSeq 2500
Description
Characterisation of the tumor extrinsic (immune-mediated) mechanisms by which panobinostat and trastuzumab can collaboratively promote tumor-associated NK cell infiltration to eradicate trastuzumab-refractory HER2+ tumors Overall design: RNA sequencing was performed on established whole AU565(pv) HER2+ human breast tumors, harvested from SCID mice 2-days post treatment initiation with vehicle (PBS/D5W), panobinostat (15mg/kg/day), trastuzumab (10mg/kg day 1) or both drugs in combination. Each treatment group comprised of 4 mice.
Publication Title
HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2<sup>+</sup> Tumors.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 24 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Ezh2 protein is the enzymatic component of the Polycomb Repressive Complex (PRC)-2, which represses its target genes by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation and differentiation during embryonic development. Recently, hot-spot mutations of Ezh2 have been identified in diffused large B cell lymphomas (DLBCLs) and follicular lymphomas (FLs). To investigate if tumor growth is dependent on the enzymatic activity of Ezh2, we have developed a potent and selective small molecule inhibitor, EI1, which inhibits the enzymatic activity of Ezh2 through direct binding and competing with the methyl group donor S-Adenosyl methionine (SAM). EI1-treated cells exhibit genome-wide loss of H3K27 methylation. Furthermore, inhibition of Ezh2 by EI1 in DLBCL cells carrying the Y641 mutations results in decreased proliferation, cell cycle arrest and apoptosis. These results provide strong validation of Ezh2 as a potential therapeutic target for the treatment of cancer with the Ezh2 mutation.
Publication Title
Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation.
Sample Metadata Fields
Disease, Cell line
View Samples- Homo sapiens
- 33 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Polycomb repressive complex (PRC) 2, containing minimally EZH2, EED and Suz12, is the H3 lysine 27 methyltransferase playing pivotal roles in transcriptional regulation. EZH2 is the catalytic subunit, and H3K27me3 activates PRC2 through binding EED to propagate the repressive mark. Cofactor SAM-competitive (SAM-C) PRC2 inhibitors (PRC2is) have been discovered to treat lymphoma and rhabdoid tumors. Here we report the discovery of EED226, a potent and selective PRC2i directly binding to the H3K27me3 pocket of EED. Upon binding, EED226 induces conformational change in EED protein. Interestingly, it inhibits both the basal and the H3K27me3-stimulated PRC2 activities. Furthermore, EED226 selectively pulled down the endogenous PRC2 complex from human cell lysates, specifically modulates H3K27 methylation and target genes similarly as SAM-C PRC2 inhibitors, and effectively regresses human lymphoma xenograft tumor in mouse. More importantly, EED226 potently inhibits the SAM-C inhibitor-resistant PRC2 and synergizes with SAM-C PRC2i in cell proliferation blocking. Together, EED226 is an inhibitor of PRC2 with a novel mechanism and represent a potential complementary strategy for PRC2-targeted cancer therapy.
Publication Title
An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 10 Downloadable Samples
- Illumina HiSeq 2000
Description
Malignant gliomas constitute one of the most significant areas of unmet medical need, due to the invariable failure of surgical eradication and their marked molecular heterogeneity. Accumulating evidence has revealed a critical contribution by the Polycomb axis of epigenetic repression. However, a coherent understanding of the regulatory networks affected by Polycomb during gliomagenesis is still lacking. Here we integrate transcriptomic and epigenomic analyses to define Polycomb-dependent networks that promote gliomagenesis, validating them both in two independent mouse models and in a large cohort of human samples. We found that Polycomb dysregulation in gliomagenesis affects transcriptional networks associated to invasiveness and de-differentiation. The dissection of these networks uncovers Zfp423 as a crtitical Polycomb-dependent transcription factor whose silencing negatively impacts survival. The anti-gliomagenic activity of Zfp423 requires interaction with the SMAD proteins within the BMP signaling pathway, pointing to a novel synergic circuit through which Polycomb inhibits BMP signaling. Overall design: Transcriptomic analysis of two different stages of gliomagenesis
Publication Title
Polycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 457 Downloadable Samples
- Illumina HiSeq 2000
Description
Transdifferentiation of fibroblasts into induced Neuronal cells (iNs) by neuronal-specific transcription factors Brn2, Myt1l and Ascl1 is a paradigmatic example of inter-lineage conversion across epigenetically distant cells. Despite tremendous progress on the transcriptional hierarchy underlying transdifferentiation, the enablers of the concomitant epigenome resetting remain to be elucidated. Here we investigated the role of KMT2A and KMT2B, two histone H3 lysine 4 methylases with cardinal roles in development, through individual and combined inactivation. We found that Kmt2b, whose human homologue's mutations cause dystonia, is selectively required for iN conversion through the suppression of the alternative myocyte program and the induction of neuronal maturation genes. Overall design: In order to study the role of KMT2A and KMT2B during transdifferentiation, we employed conditional mouse strains carrying: i) the exon 2 of Kmt2a and/or Kmt2b flanked by LoxP sites; ii) the knock-in of the YFP-coding gene into one Rosa26 allele, downstream of a LoxP-flanked transcription termination cassette (STOP cassette); and iii) the gene coding for the tamoxifen-inducible version of Cre recombinase knocked into the second Rosa26 allele (Glaser et al., 2006; Kranz et al., 2010; Testa et al., 2004). MEFs were derived from Kmt2a (and/or Kmt2b)fl/fl Cre+ YFP+ embryos and from Kmt2a+/+Kmt2b+/+ Cre+ YFP+ or Kmt2afl/+ Cre+ YFP+ for Kmt2a conditional KO (cKO) as controls (Figure 1A), and were subjected to transdifferentiation. After 13 days of BAM treatment, cells were FACS sorted for PSA-NCAM expression, and the transcriptome of positive and negative cells were independently profiled.
Publication Title
KMT2B Is Selectively Required for Neuronal Transdifferentiation, and Its Loss Exposes Dystonia Candidate Genes.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 15 Downloadable Samples
- Illumina HiSeq 2000, Affymetrix Human Gene 2.1 ST Array (hugene21st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
7q11.23 dosage-dependent dysregulation in human pluripotent stem cells affects transcriptional programs in disease-relevant lineages.
Sample Metadata Fields
Sex, Specimen part, Subject
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Gene 2.1 ST Array (hugene21st)
Description
We apply the cellular reprogramming experimental paradigm to two disorders caused by symmetrical copy number variations (CNV) of 7q11.23 and displaying a striking combination of shared as well as symmetrically opposite phenotypes: Williams Beuren syndrome (WBS) and 7q microduplication syndrome (7dup). Through a uniquely large and informative cohort of transgene-free patient-derived induced pluripotent stem cells (iPSC), along with their differentiated derivatives, we find that 7q11.23 CNV disrupt transcriptional circuits in disease-relevant pathways already at the pluripotent state. These alterations are then selectively amplified upon differentiation into disease-relevant lineages, thereby establishing the value of large iPSC cohorts in the elucidation of disease-relevant developmental pathways. In addition, we functionally define the quota of transcriptional dysregulation specifically caused by dosage imbalances in GTF2I (also known as TFII-I), a transcription factor in 7q11.23 thought to play a critical role in the two conditions, which we found associated to key repressive chromatin modifiers. Finally, we created an open-access web-based platform (accessible at http://bio.ieo.eu/wbs/ ) to make accessible our multi-layered datasets and integrate contributions by the entire community working on the molecular dissection of the 7q11.23 syndromes.
Publication Title
7q11.23 dosage-dependent dysregulation in human pluripotent stem cells affects transcriptional programs in disease-relevant lineages.
Sample Metadata Fields
Sex, Specimen part, Subject
View Samples- Arabidopsis thaliana
- 18 Downloadable Samples
- Affymetrix Arabidopsis ATH1 Genome Array (ath1121501)
Description
Functional characterization of AtWRKY72 using Arabidopsis T-DNA insertion lines showed that this gene is important for basal defense to root-knot nematode (RKN) and Hyaloperonospora parasitica arabidopsis (Hpa), but not several tested R gene-mediated defenses.To profile transcriptional reprogramming associated with AtWRKY72-dependent basal defense we used Affymetrix ATH1 GeneChips representing ~24,000 Arabidopsis genes. Three independent biological replicates were performed with Col-0, wrky72-1 and wrky72-2 plants at 96 hpt with HpaNoco2 or mock treatment. Using a false discovery rate of less than 0.05 we identified for each of these three lines genes that showed significant transcriptional changes in response to HpaNoco2 compared to the mock-treated controls. Identification of downstream targets of WRKY72 in Arabidopsis by this microarray suggests that WRKY72 uses a unique signaling pathway that involves AP2/ERF TFs independent of the ethylene signaling pathway.
Publication Title
WRKY72-type transcription factors contribute to basal immunity in tomato and Arabidopsis as well as gene-for-gene resistance mediated by the tomato R gene Mi-1.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 659 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
PDX tumors at various passages post first implantation in nude mice
Publication Title
High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response.
Sample Metadata Fields
No sample metadata fields
View Samples