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GSE11550
Homo sapiens
10 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We used microarrays to detail gene expression changes in Hs 294T human melanoma cells after treatment with elesclomol alone, or in combination with paclitaxel, to aide in identifing the mechnism of action of elesclomol.
Publication Title
Elesclomol induces cancer cell apoptosis through oxidative stress.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We used microarrays to detail gene expression changes in Hs 294T human melanoma cells after treatment with elesclomol alone, or in combination with NAC, to aide in identifing the mechnism of action of elesclomol.
Publication Title
Elesclomol induces cancer cell apoptosis through oxidative stress.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 14 Downloadable Samples
NextSeq 500
Description
Background: Here, the role of a-ketoglutarate (aKG) in the epi-metabolic control of DNA demethylation has been investigated in therapeutically relevant cardiac mesenchymal cells (CMSCs) isolated from controls and type 2 diabetes donors. Methods & results: Quantitative global analysis, methylated and hydroxymethylated DNA sequencing and gene specific GC methylation detection revealed an accumulation of 5mC, 5hmC and 5fC in the genomic DNA of human CMSCs isolated from diabetic (D) donors (D-CMSCs). Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high fat diet (HFD), injected with streptozotocin (STZ) or both in combination (STZ-HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of aKG synthesis in D-CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised thymine DNA glycosylase (TDG) and ten eleven translocation protein 1 (TET1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that aKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatched or 5fC. Accordingly, an exogenous source of aKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5fC accumulation thus partially mimicking the diabetic epigenetic landscape in cells of non- diabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of aKG-dehydrogenase, increased the aKG level in D- CMSCs and in the heart of HFD mice eliciting DNA demethylation, glucose uptake and insulin response. Conclusions: In this report we established that diabetes may epigenetically modify and compromise function of therapeutically relevant cardiac mesenchymal cells. Restoring the epi-metabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes. Overall design: Human primary cardiac mesenchymal cells (CMSC) from 7 diabetic (D) and 7 non-diabetic (ND) donors were analyzed after few rounds of ex vivo expansion. RNA was isolated and sequenced.
Publication Title
Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients: Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 4 Downloadable Samples
- Illumina HiSeq 2500
Description
NGS technology was used for high-throughput profiling of the transcriptome by comparing satellite cells lacking or not HDAC4. Overall design: Total RNA was isolated from control and HDAC4 KO satellite cells in growth conditions
Publication Title
HDAC4 regulates satellite cell proliferation and differentiation by targeting P21 and Sharp1 genes.
Sample Metadata Fields
Age, Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 37 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Albeit increased serum CK level and abnormal muscle histology are always present, boys with DMD are phenotipically indistinguishable from the normal ones at birth and, in their first years of life, acquire early motor milestones at normal times. A clear defect in muscle function becomes generally apparent by the end of the second year. As the disease is typically diagnosed between the ages of 3 and 7, the first two years are often considered and referred to as clinically presymptomatic.
Publication Title
Gene expression profiling in the early phases of DMD: a constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression.
Sample Metadata Fields
Sex, Age
View Samples- Homo sapiens
- 14 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Aplidin (plitidepsin) is a novel marine-derived antitumor agent presently undergoing phase II clinical trials in hematological malignancies and solid tumors. Lack of bone marrow toxicity has encouraged further development of this drug for treatment of leukemia and lymphoma. Multiple signaling pathways have been shown to be involved in Aplidin-induced apoptosis and cell cycle arrest in G1 and G2 phase. However, the exact mechanism(s) of Aplidin action remains to be elucidated. Here we demonstrate that mitochondria-associated or -localized processes are the potential cellular targets of Aplidin. Whole genome gene-expression profiling (GEP) revealed that fatty acid metabolism, sterol biosynthesis and energy metabolism, including the tricarboxylic acid cycle and ATP synthesis are affected by Aplidin treatment. Moreover, mutant MOLT-4, human leukemia cells lacking functional mitochondria, were found to be resistant to Aplidin. Cytosine arabinoside (araC), which also generates oxidative stress but does not affect the ATP pool, showed synergism with Aplidin in our leukemia and lymphoma models in vitro and in vivo. These studies provide new insights into the mechanism of action of Aplidin. The efficacy of the combination of Aplidin and araC is currently being evaluated in clinical phase I/II program for the treatment of patients with relapsed leukemia and high-grade lymphoma.
Publication Title
Aplidin synergizes with cytosine arabinoside: functional relevance of mitochondria in Aplidin-induced cytotoxicity.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 147 Downloadable Samples
- Illumina HiSeq 2000
Description
The transcriptional response to many widely used drugs and its modulation by genetic variability is poorly understood. Here we present an analysis of RNAseq profiles from heart tissue of 18 inbred mouse strains treated with the ß-blocker atenolol (ATE) and the ß-agonist isoproterenol (ISO). Differential expression analyses revealed a large set of genes responding to ISO (n=1770 at FDR=0.0001) and a comparatively small one responding to ATE (n=23 at FDR=0.0001). At a less stringent definition of differential expression, the transcriptional responses to these two antagonistic drugs are reciprocal for many genes, with an overall anti-correlation of r= -0.3. This trend is also observed at the level of most individual strains even though the power to detect differential expression is significantly reduced. The inversely expressed gene sets are enriched with genes annotated for heart-related functions. Modular analysis revealed gene sets that exhibited coherent transcription profiles across some strains and/or treatments. Correlations between such modules and a broad spectrum of cardiovascular traits are stronger than expected by chance. This provides evidence for the overall importance of transcriptional regulation for these organismal responses and explicits links between co-expressed genes and the traits they are associated with. Gene set enrichment analysis of differentially expressed groups of genes pointed to pathways related to heart development and functionality. Our study provides new insights into the transcriptional response of the heart to perturbations of the ß-adrenergic system, implicating several new genes that had not been associated to this system previously. Overall design: Cardiac mRNA expression profiles of the various inbred mouse strains were examined either under baseline condition (control) or in response to chronic administration of isoproterenol or atenolol at 10 mg/kg per day for 2 weeks. Expression data were produced by RNA-sequencing, in triplicates, using the HiSeq 2000 Illumina platform. Only males, aged ten to twelve weeks on average, were included in the experimental protocol. Mouse ID numbers refer to those described in Berthonneche C. et al. PLoS One. 2009 Aug 12;4(8):e6610 (doi: 10.1371/journal.pone.0006610. PMID: 19672458). Corresponding individual phenotypic values, in particular heart rate, systolic blood pressure, electrocardiogaphic measurements and heart weight are available in dataset "maurer1" of the Mouse Phenome Database (http://phenome.jax.org/). Preparation of the sequencing libraries, RNA-sequencing and RNA expression quantitations were performed by the BGI.
Publication Title
RNAseq analysis of heart tissue from mice treated with atenolol and isoproterenol reveals a reciprocal transcriptional response.
Sample Metadata Fields
Sex, Specimen part, Treatment, Subject
View Samples- Homo sapiens
- 36 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Dose and time course response of lapatinib in breast cancer cell lines.
Publication Title
Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles.
Sample Metadata Fields
Disease, Disease stage, Cell line, Compound, Time
View Samples- Caenorhabditis elegans
- 6 Downloadable Samples
- Affymetrix C. elegans Genome Array (celegans)
Description
We used Au nanoparticles (Au-NPs) as a model for studying particle specific effects of manufactured nanomaterials (MNMs) by examining the toxicogenomic responses in a model soil organism, free living nematode Caenorhabditis elegans. Global genome expression for nematodes exposed to 4-nm citrate-coated Au-NPs at the LC10 (5.9 mg L-1) revealed significant differential expression of 797 genes. The levels of expression for five genes (apl-1, dyn-1, act-5, abu-11, and hsp-4) were confirmed independently with qRT-PCR. Seven common biological pathways associated with 38 of these genes were identified. Activation of 26 pqn/abu genes from noncanonical Unfolded Protein Response (UPR) pathway and up-regulation of molecular chaperones (hsp-16.1, hsp-70, hsp-3 and hsp-4) were observed and are likely indicative of endoplasmic reticulum stress. Inhibition of abu-11 with RNAi showed increase in mortality in Au-NP exposed nematodes suggesting possible involvement of abu-11 (a gene associated with specific to C. elegans UPR) in a protective mechanism against Au-NPs. Exposure to Au-NPs also caused activation of genes involved in apoptosis and necrosis and resulted ultimately in 10% mortality. These results demonstrate that Au-NPs are bioavailable and cause adverse effects to a model ecoreceptor which activate both general and specific biological pathways.
Publication Title
Toxicogenomic responses of the model organism Caenorhabditis elegans to gold nanoparticles.
Sample Metadata Fields
Treatment
View Samples- Homo sapiens
- 4 Downloadable Samples
- Illumina HiSeq 2000
Description
In this work, we showed that the re-expression of miR-26a in DU-145 prostate cancer cells restored the tumor suppressor activity of miR-26a. To discover the genes and pathways elicited by miR-26a re-expression, we used the miRNA pull out assay to capture and the Next Generation Sequencing to identify the miR-26a targets. Data showed that: i) miR-26a captured both non-coding and coding RNAs; ii) 46% of transcripts were putative miR-26a targets according to target prediction algorithms; iii) 21 pathways were significantly enriched and the “Pathway in Cancer” was among those comprising the largest number of genes, including BIRC5 that we experimentally validated. Accordingly, the detection of cell proliferation-related events showed that miR-26a exerted its tumor suppressor activity at several levels, by decreasing the survival, impairing the migration of tumor cells and by inducing both apoptosis and cell cycle block. In conclusion, we showed that the collection of miR-26a interacting transcripts (miR-26a/targetome) represented a fruitful platform to decipher the miR-26a-dependent gene expression networks. In perspective the availability of miRNA-specific and tumor-specific targetomes will allow the discovery of new druggable tumor genes and pathways. Overall design: The miRNA pull out assay was performed modifying the protocol described by Orom et al. {Methods 43, 162-165, doi:S1046-2023(07)00097-7}. DU-145 were seeded into the wells of a 6-well at the density of 1.5 x105. After 24 hours from seeding, cells were transfected using lipofectamine (Thermo Fisher) with 60nM of either miR-26a duplex (ds-miR-26aCT) or a mix of 3' biotin-tagged miR-26a 7tU (nucleotide 7 was a thiouridine) and miR-26a 17tU duplexes (ds-miR-26aBIO). The day after transfection, the cells were washed with PBS and irradiated with UV (365nm, 2J/cm2), using the Bio-Link crosslinking (BLX) (Ambrose Lourmat) with appropriate UV lamps, to induce cross-linking of tU nucleotides to RNA. Total RNA was extracted adding directly on adherent cells TRIzol reagent (Thermo Fisher) and following the instructions provided by the manufacturer. After DNAse treatment, 15 µg of RNA was incubated for 4 hrs at 4°C with 100 µl of streptavidin-conjugated beads (200 µl of Streptavidin Sepharose high performance, GE Healthcare) previously suspended in PO buffer (1M Tris pH8, 5M NaCl, 1M MgCl2, NP40 50 µl in 100 ml buffer). After 2 washes with PO buffer and 2 washes with DEPC-treated water, the RNA complexed with beads was recovered by adding 1 ml Trizol directly on the beads and then following the TRIzol RNA extraction protocol. We performed two biological replicates obtaining two miR-26aCT (control) and two miR-26aBIO (miR-26a) pull out samples. The RNA isolated after the miRNA pullout procedure from both miR-26aCT and miR-26aBIO samples was used for the construction of the cDNA libraries using the TruSeq Stranded Total RNA Sample Preparation kit (Illumina) according to the manufacturer's suggestions. cDNA libraries were sequenced by HiSeq2000 (Illumina) in single-reads mode (50bp) by IGA Technology Service, Udine, Italy, obtaining about 20 million of reads for each samples.
Publication Title
Discovering the miR-26a-5p Targetome in Prostate Cancer Cells.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples