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SRP110515
Caenorhabditis elegans
30 Downloadable Samples
Illumina HiSeq 2000
Description
HIV-1 nucleoside reverse transcriptase inhibitor (NRTI) use is associated with severe adverse events. However, the exact mechanisms behind their toxicity has not been fully understood. Mitochondrial dysfunction after chronic exposure to NRTIs has predominantly been assigned to mitochondrial polymerase-? inhibition by NRTIs. However, an increasing amount of data suggests that this is not the sole mechanism. Many NRTI induced adverse events have been linked to the incurrence of oxidative stress, although the causality of events leading to reactive oxygen species (ROS) production and their role in toxicity is unclear. In this study we show that short-term effects of these drugs, which are rarely discussed in the literature, include direct inhibition of the mitochondrial respiratory chain (MRC), decreased ATP levels and increased ROS production. Collectively these events affect fitness and longevity of C. elegans through mitohormetic signalling events. Furthermore, we demonstrate that these effects can be normalized by addition of the anti-oxidant N-acetylcysteine (NAC), which suggests that ROS likely influence the onset and severity of adverse events upon drug exposure. Overall design: RNA-seq on Caenorhabditis elegans exposed to DMSO, 3''-azido-3''-deoxythymidine (zidovudine or AZT), 2'',3''-didehydro-2'',3''-deoxythymidine (stavudine or d4T), 3''-deoxy-3''-fluorothymidine (alovudine or FLT) or untreated control after 24 or 72 hours of exposure.
Publication Title
Beyond the polymerase-γ theory: Production of ROS as a mode of NRTI-induced mitochondrial toxicity.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 2000
Description
Inactivating mutations in the zinc finger gene PHF6 are seen in approximately 40% of adult T-cell acute lymphoblastic leukemias (T-ALLs) and 3% of adult acute myeloid leukemias (AMLs). The absence of PHF6 mutations in B-cell lineage malignancies has led to the hypothesis that PHF6 may act as a lineage-specific tumor suppressor gene. Here, we demonstrate that PHF6 plays a critical role in regulating B-cell identity in the context of B-cell precursor acute lymphoblastic leukemia (preB-ALL). Transplantation of Phf6 knockout preB-ALL cells (hereafter referred to as Phf6KO cells) into immunocompetent syngeneic recipients resulted in the development of a fully penetrant lymphoma-like disease. Strikingly, the resulting lymphomas showed robust up-regulation of the canonical T-cell marker CD4, suggesting that Phf6KO cells adopt a T-cell program in the context of leukemogenesis. RNA sequencing analysis revealed numerous differentially expressed (DE) genes in Phf6WT and Phf6KO cells, including a significant down-regulation of genes and gene sets involved in pathways important for B-cell development. Chromatin immunoprecipitation followed by high-throughput sequencing analysis revealed that PHF6 co-localizes with H3K27ac signals close to the transcription start sites (TSSs) and enhancer regions of a significant proportion of DE genes. Notably, regions flanking the TSS of DE genes showed significant enrichment for binding sites of several well-described master regulators of B-cell development, including PU.1, EGR-1, EBF-1, NF-kB, TCF3 and TCF12. We found that PHF6 and TCF12 physically interact in preB-ALL cells, suggesting that these factors act synergistically in the establishment and maintenance of B-cell identity. In addition, we found that a human PHF6 mutant T-ALL cell line has an incompletely rearranged IGH locus, strongly suggesting that T-ALL can have a B-cell origin. These findings reveal an essential role for PHF6 in the establishment and maintenance of B-cell identity in preB-ALL by directly activating genes that are crucial for B-cell lineage commitment and maintenance. Collectively, these results indicate that loss of function of PHF6 in preB-ALL leads to an unstable cellular state in which cells acquire alternate developmental programs (such as the T-lineage program) to survive, potentially explaining the apparent absence of PHF6 mutations in human B cell-lineage malignancies. Overall design: Gene expression profiles by RNA-Seq of 3 Phf6 wild-type preB-ALL cells, 3 shPhf6 preB-ALL cells, 6 Phf6 knockout (2 different sgRNAs) preB-ALL cells
Publication Title
PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 9 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Fibroadenomas are the most common benign breast tumors in women under 30. Unlike their malignant counterparts, relatively molecular profiling has been done on fibroadenomas. Here we performed gene expression profiling on ten fibroadenomas in order to better characterize these tumors. Through targeted amplicon sequencing, we have found that six of these tumors have MED12 mutations. We show that the MED12 mutations, among others, are associated with activated estrogen signaling, as well as increased invasiveness through upregulation of ECM remodelling genes.
Publication Title
Exome sequencing identifies highly recurrent MED12 somatic mutations in breast fibroadenoma.
Sample Metadata Fields
Age
View Samples- Homo sapiens
- 294 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
A formalin-fixed paraffin-embedded (FFPE)-based prognostic signature to predict metastasis in clinically low risk stage I/II microsatellite stable colorectal cancer.
Sample Metadata Fields
Sex, Age
View Samples- Homo sapiens
- 150 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This study was conducted in order to identify biomarkers for a prognostic gene expression signature for metastases in early stage CRC.
Publication Title
A formalin-fixed paraffin-embedded (FFPE)-based prognostic signature to predict metastasis in clinically low risk stage I/II microsatellite stable colorectal cancer.
Sample Metadata Fields
Sex, Age
View Samples- Saccharomyces cerevisiae
- 4 Downloadable Samples
- Illumina HiSeq 2500
Description
This analysis identified 27 genes that are induced, and 29 that are repressed, by a factor of two or more in Asr1RING mutant cells. Genes in each category did not cluster according to gene ontology or chromosome, but we did notice that 33% of genes in the induced set lie within 50 kb of a telomere. In contrast, for repressed genes, only 7% were similarly telomere-proximal. The induction of subtelomeric gene expression in Asr1RING mutant cells suggests that the Ub-ligase activity of Asr1 may be required for authentic patterns of subtelomeric gene silencing. Overall design: Transcriptome of WT and Asr1 RING mutant cells grown at log phase in enriched media.
Publication Title
Antagonistic roles for the ubiquitin ligase Asr1 and the ubiquitin-specific protease Ubp3 in subtelomeric gene silencing.
Sample Metadata Fields
Subject
View Samples- Homo sapiens
- 61 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Tumors of advanced gastric cancer patients were biopsied and subjected to gene expression profiling using the Affymetrix Human Genome U133 Plus 2.0 Arrays. Patients were then segregated into G1, G2 or G3 groups based on their tumor genomic profiles. Patients in the G1 and G3 cohorts were assigned SOX (oxaliplatin plus S-1) chemotherapy whereas those in the G2 cohort were given SP (cisplatin plus S-1) regimen.
Publication Title
Real-Time Tumor Gene Expression Profiling to Direct Gastric Cancer Chemotherapy: Proof-of-Concept "3G" Trial.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 20 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
ST3GAL1-Associated Transcriptomic Program in Glioblastoma Tumor Growth, Invasion, and Prognosis.
Sample Metadata Fields
Disease stage
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Cell surface sialylation confers many roles in cancer biology including cell proliferation, invasiveness, metastasis and angiogenesis. We show here that ST3Gal1 sialyltransferase marks a self-renewing cellular fraction. Depletion of ST3GAL1 abrogates glioma cell growth and tumorigenicity. In contrast, TGFb induces ST3GAL1 expression and correlates with the pattern of ST3Gal1 activation in patient tumors of the mesenchymal molecular subtype. To delineate the downstream events of ST3Gal1 signaling, we utilized a bioinformatical approach that leveraged on the greater statistical power of large patient databases, and subsequently verified our predictions in patient-derived glioma cells. We identify FoxM1, a major stem cell regulatory gene, as a downstream effector, and show that ST3Gal1 mediates the glioma phenotype through control of FoxM1 protein degradation
Publication Title
ST3GAL1-Associated Transcriptomic Program in Glioblastoma Tumor Growth, Invasion, and Prognosis.
Sample Metadata Fields
Disease stage
View Samples- Homo sapiens
- 13 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
In these microarray experiments, we characterize the gene expression of mammary epithelial cells (MCF10A cells) grown in either a traditional monolayer cell culture setting (2D) or on Matrigel, which induces single MCF10A cells to form organized acinar structures (3D). Morphogenesis of mammary epithelial cells into organized acinar structures in vitro is accompanied by widespread changes in gene expression patterns, including a substantial decrease in expression of Myc.
Publication Title
Epithelial cell organization suppresses Myc function by attenuating Myc expression.
Sample Metadata Fields
Specimen part, Cell line, Time
View Samples