Microarray data allowed detection of genes that are induced by light in the zebrafish pineal gland
The light-induced transcriptome of the zebrafish pineal gland reveals complex regulation of the circadian clockwork by light.
Sex, Specimen part, Treatment, Time
View SamplesYin Yang 1 (YY1) is a multifunctional zinc-finger-containing transcription factor that plays crucial roles in numerous biological processes by selectively activating or repressing transcription, depending upon promoter contextual differences and specific protein interactions. In mice, Yy1 null mutants die early in gestation while Yy1 hypomorphs die at birth from lung defects. We studied how the epithelial-specific inactivation of Yy1 impacts on lung development. The Yy1 mutation in lung epithelium resulted in neonatal death due to respiratory failure. It impaired tracheal cartilage formation, altered cell differentiation, abrogated lung branching, and caused airway dilation similar to those seen in human congenital cystic lung diseases. The cystic lung phenotype in Yy1 mutants can be explained by the reduced expression of Shh in lung endoderm, a transcriptional target of YY1, and the subsequent derepression of mesenchymal Fgf10 expression. Accordingly, SHH supplementation partially rescued the lung phenotype in vitro. Analysis of human lung tissues revealed decreased YY1 expression in children with pleuropulmonary blastoma (PPB), a rare pediatric lung tumor arising during fetal development and associated with DICER1 mutations. No evidence for a potential genetic interplay between murine Dicer and Yy1 genes during lung morphogenesis was observed. However, the cystic lung phenotype resulting from the epithelial inactivation of Dicer function mimics the Yy1 lung malformations with similar changes in Shh and Fgf10 expression. Together, our data demonstrate the critical requirement for YY1 in lung morphogenesis and identify Yy1 mutant mice as a potential model for studying the genetic basis of PPB.
Epithelial inactivation of Yy1 abrogates lung branching morphogenesis.
Specimen part
View SamplesInactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16INK4a-deficient profile associated with positive responses to CDK4/6 inhibitors. Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT. Moreover, our study suggests a novel paradigm whereby critically low oncogene levels, caused by loss of a driver tumor suppressor, may also be exploited therapeutically. Overall design: The effect of CDK6 knockdown and palbociclib treatment on SCCOHT cells.
CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary.
Specimen part, Treatment, Subject
View SamplesEpithelial/mesenchymal transition (EMT) is associated with loss of cell adhesion molecules, such as E-cadherin, and increased invasion, migration, and proliferation in epithelial cancers. In non-small cell lung cancer (NSCLC), EMT is associated with greater resistance to EGFR inhibitors. However, its potential to predict response to other targeted drugs or chemotherapy has not been well characterized. The goal of this study was to develop a robust, platform-independent EMT gene expression signature and to investigate the association of EMT and drug response in NSCLC.
An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance.
Sex, Disease, Treatment, Race
View SamplesInfection with non-cytopathic bovine viral diarrhea virus (ncpBVDV) is associated with uterine disease and infertility. This study investigated the influence of ncpBVDV on immune functions of the bovine endometrium by testing the response to bacterial lipopolysaccharide (LPS) at the level of whole-transcriptomic gene expression. Analysis showed that approximately 30% of the 1,006 genes altered by LPS are involved in immune response. Many innate immune genes that typically respond to LPS were inhibited by ncpBVDV including those involved in pathogen recognition, inflammation, interferon response, chemokines, tissue remodeling, cell migration and cell death/survival. Infection with ncpBVDV can thus compromise immune function and pregnancy recognition thereby potentially predisposing infected cows to postpartum bacterial endometritis and reduced fertility.
Global transcriptomic profiling of bovine endometrial immune response in vitro. I. Effect of lipopolysaccharide on innate immunity.
Sex, Treatment
View SamplesThe human steroid receptor RNA activator (SRA) gene encodes both non-coding RNAs (ncRNAs) and protein-generating isoforms. However, the breadth of endogenous target genes that might be regulated by SRA RNAs remains largely unknown. To address this, we depleted SRA RNA in two human cancer cell lines (HeLa and MCF-7) with small interfering RNAs, then assayed for changes in gene expression by microarray analyses using Affymetrix HGU133+2 arrays. We also tested if SRA depletion affects estradiol-regulated genes in MCF-7 breast cancer cells.
Research resource: expression profiling reveals unexpected targets and functions of the human steroid receptor RNA activator (SRA) gene.
Cell line
View SamplesBackground: Local recurrence is the major manifestation of treatment failure in patients with operable laryngeal carcinoma. Established clinicopathological factors cannot sufficiently predict patients that are likely to recur after treatment. Additional tools are therefore required to accurately identify patients at high risk for recurrence. Methods: Using Affymetrix U133A Genechips, we profiled fresh-frozen tumor tissues from 59 patients with operable laryngeal cancer. All patients were treated locally with surgery, with or without radiation therapy. We performed Cox regression proportional hazards modeling to identify multigene predictors of recurrence. The end-point of our analysis was disease-free survival (DFS). Gene models were directly validated in a separate, similarly treated cohort of 50 patients using Affymetrix chips. In an attempt to further validate our results, we profiled 12 selected genes of our model in formalin-fixed tumor tissues from an independent cohort of 75 patients, using quantitative real time-polymerase chain reaction (qRT-PCR). Results: We focused on genes univariately associated with DFS (p<0.05) in the training set. Among several gene models comprising different numbers of genes, a 30-gene model demonstrated optimal performance (log-rank, p<0.001). We directly applied these gene models to the validation set, after adjusting for non-biological experimental variability, and observed similar results. Specifically, median DFS, as predicted by the 30-gene model, was 34 and 80 months for high- and low-risk patients, respectively (p=0.01). Hazard Ratio (HR) for recurrence for the high-risk group was 3.87 (95% CI 1.28-11.73, p=0.017). Furthermore, unsupervised hierarchical clustering of the 75 patients, based on the qRT-PCR 12-gene profile, yielded two groups, which differed significantly in DFS (log-rank, p=0.027). HR= for recurrence was 2.26, (95% CI 1.08-4.76, p=0.031). Conclusion: We have established and validated gene models that can successfully stratify patients with laryngeal cancer, based on their risk for recurrence. Thus, patients with unfavorable prognosis, when accurately identified, could be ideal candidates for the application of more aggressive treatment modalities.
Identification and validation of a multigene predictor of recurrence in primary laryngeal cancer.
Age, Specimen part, Disease stage
View SamplesWe performed gene expression profilings of platelet-derived growth factor subunit B (PDGFB)-induced mouse glioma to compare the differential transcriptome profiles between Ctrl-T tumor cells and Olig2cKO tumor cells. Overall design: Expression profiling of Ctrl-T and Olig2cKO brain tumor (glioma) cells, normal oligodendrocyte progenitor cells (OPCs), normal astrocytes, and normal brain cortex by high-throughput sequencing.
Olig2-Dependent Reciprocal Shift in PDGF and EGF Receptor Signaling Regulates Tumor Phenotype and Mitotic Growth in Malignant Glioma.
Specimen part, Subject
View SamplesWe performed gene expression pofiling of of Olig2cKO and control glioma tumor and identified significantly changed genes Overall design: RNA-seq of control tumor tissues and Olig2cKO tumor tissues
Olig2-Dependent Reciprocal Shift in PDGF and EGF Receptor Signaling Regulates Tumor Phenotype and Mitotic Growth in Malignant Glioma.
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View SamplesWe aimed to predict obesity risk with genetic data, specifically, obesity-associated gene expression profiles. Genetic risk score was computed. The genetic risk score was significantly correlated with BMI when an optimization algorithm was used. Linear regression and built support vector machine models predicted obesity risk using gene expression profiles and the genetic risk score with a new mathematical method.
A computational framework for predicting obesity risk based on optimizing and integrating genetic risk score and gene expression profiles.
Specimen part
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