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GSE28266
Homo sapiens
7 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Chromosomal instability in early cancer stages is caused by stress on DNA replication. The molecular basis for replication perturbation in this context is currently unknown. We studied the replication dynamics in cells in which a regulator of S-phase entry and cell proliferation, the Rb-E2F pathway, is aberrantly activated. Aberrant activation of this pathway by HPV-16 E6/E7 or cyclin E oncogenes, significantly decreased the cellular nucleotide levels in the newly transformed cells. Exogenously supplied nucleosides rescued the replication stress and DNA damage, and dramatically decreased oncogene-induced transformation. Increased transcription of nucleotide biosynthesis genes, mediated by expressing the transcription factor c-Myc, increased the nucleotide pool and also rescued the replication-induced DNA damage. Our results suggest a model for early oncogenesis in which uncoordinated activation of factors regulating cell proliferation leads to insufficient nucleotides that fail to support normal replication and genome stability.
Publication Title
Nucleotide deficiency promotes genomic instability in early stages of cancer development.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 5 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
The tumorigenicity of human pluripotent stem cells (hPSCs) is a major safety concern for their application in regenerative medicine. Here we identify the tight-junction protein Claudin-6 as a specific cell surface marker of hPSCs that can be used to selectively remove Claudin-6-positive cells from mixed cultures. We show that Claudin-6 is absent in adult tissues but highly expressed in undifferentiated cells, where it is dispensable for hPSC survival and self-renewal. We use three different strategies to remove Claudin-6-positive cells from mixed populations: an antibody against Claudin-6; a cytotoxin-conjugated antibody that selectively targets undifferentiated cells; and clostridium perfringens enterotoxin, a toxin that binds several Claudins, including Claudin-6, and efficiently kills undifferentiated cells, thus eliminating the tumorigenic potential of hPSC-containing cultures. This work provides a proof of concept for the use of Claudin-6 to eliminate residual undifferentiated hPSCs from culture, highlighting a strategy that may increase the safety of hPSC-based cell therapies.
Publication Title
Immunologic and chemical targeting of the tight-junction protein Claudin-6 eliminates tumorigenic human pluripotent stem cells.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The tetracycline antibiotics are widely used in biomedical research as mediators of inducible gene expression systems. Despite many known effects of tetracyclines on mammalian cells -- including inhibition of the mitochondrial ribosome -- there have been few reports on potential off-target effects at concentrations commonly used in inducible systems. Here, we report that in human cell lines, commonly used concentrations of doxycycline change gene expression patterns and concomitantly shift metabolism towards a more glycolytic phenotype, evidenced by increased lactate secretion and reduced oxygen consumption. We also show that these concentrations are sufficient to slow proliferation and alter cell cycle progression in vitro. These findings suggest that researchers using doxycycline in inducible expression systems should design appropriate controls to account for potential confounding effects of the drug on cellular metabolism.
Publication Title
Doxycycline alters metabolism and proliferation of human cell lines.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 3 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Pluripotent-specific inhibitors (PluriSIns) make a powerful tool for studying the mechanisms that control the survival of human pluripotent stem cells (hPSCs). Here we characterize PluriSIn#2 as a novel selective indirect inhibitor of topoisomerase II alpha (TOP2A). We find that TOP2A is uniquely expressed in undifferentiated hPSCs, and that its inhibition results in their rapid cell death. These findings reveal a dependency of hPSCs on the activity of TOP2A, which can be harnessed for their selective elimination from culture.
Publication Title
Brief reports: Controlling the survival of human pluripotent stem cells by small molecule-based targeting of topoisomerase II alpha.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Caenorhabditis elegans
- 12 Downloadable Samples
Affymetrix C. elegans Gene 1.0 ST Array (elegene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Toxicogenomics of iron oxide nanoparticles in the nematode C. elegans.
Sample Metadata Fields
Specimen part
View Samples- Caenorhabditis elegans
- 6 Downloadable Samples
- Affymetrix C. elegans Gene 1.0 ST Array (elegene10st)
Description
Superparamagnetic Iron Oxide Nanoparticles (SPIONs) are currently being investigated for a range of biomedical applications. Their use have been related with different cytotoxic mechanisms including the generation of oxidative stress and the induction of metal detoxification pathways, among others. We have investigated the molecular mechanisms responsive to in-house fabricated citrate coated SPIONs (C-SPIONs) in the nematode C. elegans to compare in vivo findings with previous in vitro studies. C-SPIONs (500 g/ml) affected the transcriptional response of signal transduction cascades (i.e. TFG-beta), protein processing in the endoplasmic reticulum, and RNA transport, among other biological processes. They also triggered a lysosomal response, indicating a relevant biological role of this cellular compartment in the response to this nanoparticle treatment in C. elegans. Interestingly, other pathways frequently linked to nanotoxicity like oxidative stress or apoptosis were not identified as significantly affected in this genome-wide in vivo study despite the high dose of exposure.
Publication Title
Toxicogenomics of iron oxide nanoparticles in the nematode C. elegans.
Sample Metadata Fields
Specimen part
View Samples- Caenorhabditis elegans
- 6 Downloadable Samples
- Affymetrix C. elegans Gene 1.0 ST Array (elegene10st)
Description
Superparamagnetic Iron Oxide Nanoparticles (SPIONs) are currently being investigated for a range of biomedical applications. Their use have been related with different cytotoxic mechanisms including the generation of oxidative stress and the induction of metal detoxification pathways, among others. Different NP coatings are being explored, among them albumin which has been applied in some drugs delivery systems. We have investigated the molecular mechanisms responsive to in-house fabricated SPIONs coated with bovine serum albumin (BSA-SPIONs) in the nematode C. elegans to compare in vivo findings with previous in vitro studies. BSA-SPIONs (500 g/ml) affected the transcriptional response of glycan metabolic pathways related to innate immune response, xenobiotics degradation, and triggered a lysosomal response, indicating a relevant biological role of this cellular compartment in the response to this nanoparticle treatment in C. elegans. Remarkably, key biological functions such as apoptosis or protein processing were not affected with significance despite the high dose of exposure.
Publication Title
Toxicogenomics of iron oxide nanoparticles in the nematode C. elegans.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Illumina HiSeq 2000
Description
The C2H2 zinc finger is the most prevalent DNA-binding motif in the mammalian proteome, with DNA-binding domains usually containing more tandem fingers than are needed for stable sequence-specific DNA recognition. To examine the reason for the frequent presence of multiple zinc fingers, we generated mice lacking finger 1 or finger 4 of the 4-finger DNA-binding domain of Ikaros, a critical regulator of lymphopoiesis and leukemogenesis. Each mutant strain exhibited a specific subset of the phenotypes observed with Ikaros null mice. Of particular relevance, fingers 1 and 4 contributed to distinct stages of B- and T-cell development and finger 4 was selectively required for tumor suppression in thymocytes and in a new model of BCR-ABL+ acute lymphoblastic leukemia. These results, combined with transcriptome profiling (this GEO submission: RNA-Seg of whole thymus from wt and the two ZnF mutants), reveal that different subsets of fingers within multi-finger transcription factors can regulate distinct target genes and biological functions, and they demonstrate that selective mutagenesis can facilitate efforts to elucidate the functions and mechanisms of action of this prevalent class of factors. Overall design: Ikaros RNA-Seq from double positive thymocytes comparing wt (n=2), Ikaros-ZnF1-/- mutant (n=2) and Ikaros-ZnF4-/- mutant (n=2)
Publication Title
Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros.
Sample Metadata Fields
Sex, Age, Specimen part, Cell line, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2000
Description
The C2H2 zinc finger is the most prevalent DNA-binding motif in the mammalian proteome, with DNA-binding domains usually containing more tandem fingers than are needed for stable sequence-specific DNA recognition. To examine the reason for the frequent presence of multiple zinc fingers, we generated mice lacking finger 1 or finger 4 of the 4-finger DNA-binding domain of Ikaros, a critical regulator of lymphopoiesis and leukemogenesis. Each mutant strain exhibited a specific subset of the phenotypes observed with Ikaros null mice. Of particular relevance, fingers 1 and 4 contributed to distinct stages of B- and T-cell development and finger 4 was selectively required for tumor suppression in thymocytes and in a new model of BCR-ABL+ acute lymphoblastic leukemia. These results, combined with transcriptome profiling (this GEO submission: RNA-Seg of whole thymus from wt and the two ZnF mutants), reveal that different subsets of fingers within multi-finger transcription factors can regulate distinct target genes and biological functions, and they demonstrate that selective mutagenesis can facilitate efforts to elucidate the functions and mechanisms of action of this prevalent class of factors. Overall design: RNA-Seq from sorted primary proB cell Hardy Fractions B and C+C'', comparing wt, Ikaros-ZnF1-/- mutant and Ikaros-ZnF4-/- mutant.
Publication Title
Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Sus scrofa
- 25 Downloadable Samples
- Affymetrix Porcine Genome Array (porcine)
Description
Postweaning multisystemic wasting syndrome (PMWS) is one of the pig diseases with major economic impact worldwide. Clinical, pathologic and some immunologic aspects of this disease are well-known, but the molecular mechanisms underlying pathogenic mechanisms of the disease are still poorly understood. The objective of the present study was to investigate the global changes in gene expression in the mediastinal lymph nodes from pigs naturally affected by PMWS and healthy counterparts, using the Affymetrix Porcine Genechip. This is the first study on gene expression in pigs naturally affected by PMWS. The present results allowed identifying potential mechanisms underlying the inflammation, lymphocyte depletion in lymphoid tissues and immune suppression, which are key features of PMWS.
Publication Title
Microarray analysis of mediastinal lymph node of pigs naturally affected by postweaning multisystemic wasting syndrome.
Sample Metadata Fields
Age, Specimen part, Disease, Disease stage
View Samples