Genetically engineered mouse models of cancer represent valuable biological tools that can be used to filter genome-wide expression datasets generated from human prostate tumours, and identify gene expression alterations that are functionally important to cancer development and progression. In this study, we have generated RNASeq data from tumours arising in two established mouse models of prostate cancer, PB-Cre/PtenloxP/loxP and p53loxP/loxPRbloxP/loxP, and integrated this with published human prostate cancer expression data to pinpoint cancer-associated gene expression changes that are conserved between the two species. In order to identify potential therapeutic targets, we then filtered this information for genes that are either known or predicted to be druggable. Using this approach, we identified the serine/threonine kinase MELK as a potential therapeutic target in prostate cancer. MELK was overexpressed in both human and murine prostate cancers, and high expression of MELK was associated with biochemical recurrence in prostate cancer patients. Overall design: 92 Samples
Identification of potential therapeutic targets in prostate cancer through a cross-species approach.
Cell line, Subject
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Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer.
Specimen part, Cell line
View SamplesBeta-arrestin 1 (ARRB1) has been implicated in transcriptional regulation as part of protein complexes bound to chromatin. Here we investigate its effect on transcription and its potential impact on prostate cancer. We report the first genome-wide mapping of chromatin binding for ARRB1 and combine it with expression array data to define its transcriptome. We identify Hypoxia Inducible Factor 1A (HIF1A) as a nuclear binding partner that recruits ARRB1 to promoter regions of HIF1A targets. We show that ARRB1 modulates HIF1A-dependent transcription and promotes a shift in cellular metabolism from oxidative phosphorylation to aerobic glycolysis. In addition, we show that ARRB1 plays an important role in neoplastic transformation, cell growth and resistance to hypoxic stress. This is the first example of an endocytic adaptor protein regulating metabolic pathways and implicates ARRB1 as a tumour promoter.
Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer.
Specimen part, Cell line
View SamplesAnalysis of C4-2 Prostate cancer cell line after 72 hours of knockdown. CHKA is overexpressed in a number of solid tumours, including prostate cancer. Results provide insight into the molecular mechanisms of CHKA in prostate carcinogenesis. Overall design: This experiment was designed to understand the regulation of transcriptome by Choline kinase alpha (CHKA) which is an important enzyme in Kennedy pathway. In order to achieve this, the endogenous protein was knocked down using siRNA pool that targets the CHKA mRNA.
Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target.
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View SamplesGerminal center (CD19+Fas+GL7+) and naive (CD19+Fas-GL7-) B cells were sorted from Peyer''s patches of littermate 12 weeks old WT C57BL/6 mice. Three biological replicates were analyzed, each composed of a pool of 5 female mice. RNA was purified from pellets of 2-2.5x10^4 cells and sequencing libraries were prepared from 100ng of total RNA per replicate. Overall design: Transcriptional profiling of germinal center and naive B cells from Peyer's patches of WT mice.
A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets.
Sex, Age, Specimen part, Cell line, Subject
View SamplesMechanisms of immune regulation may control proliferation of aberrant plasma cells (PCs) in patients with the asymptomatic monoclonal gammopathy of undetermined significance (MGUS) preventing progression to active multiple myeloma (MM). We investigated the role of CD85j (LILRB1), an inhibitory immune checkpoint for B cell function, in MM pathogenesis.
Loss of the Immune Checkpoint CD85j/LILRB1 on Malignant Plasma Cells Contributes to Immune Escape in Multiple Myeloma.
Specimen part, Cell line
View SamplesBackground: Transcriptome variability is due to genetic and environmental causes, much like any other complex phenotype. Ascertaining the transcriptome differences between individuals is an important step to understand how selection and genetic drift may affect gene expression. To that end, extant divergent livestock breeds offer an ideal genetic material.
Impact of breed and sex on porcine endocrine transcriptome: a bayesian biometrical analysis.
Sex, Specimen part
View SamplesData present the expression analysis of different mouse ES cell line with altered expression of GTF2I.
TFII-I regulates target genes in the PI-3K and TGF-β signaling pathways through a novel DNA binding motif.
Specimen part
View SamplesMutations in PROP1 are the most common cause of hypopituitarism in humans; therefore, unraveling its mechanism of action is highly relevant from a therapeutic perspective. Our current understanding of the role of PROP1 in the pituitary gland is limited to the regulation of pituitary transcription factors Hesx1 and Pit1. To elucidate the comprehensive PROP1-dependent gene regulatory network, we conducted genome wide analysis of PROP1 DNA binding and effects on gene expression in mutant tissues, isolated stem cells and engineered cell lines. We determined that PROP1 is essential for maintaining proliferation of stem cells and stimulating them to undergo an epithelial to mesenchymal transition-like process necessary for cell migration and differentiation. Genomic profiling reveals that PROP1 binds to and represses claudin 23, characteristic of epithelial cells, and it activates EMT inducer genes: Zeb2, Notch2 and Gli2. Our findings identify PROP1 as a central transcriptional component of pituitary stem cell differentiation. Overall design: Pituitary Colony forming cells mRNA of 13-day old wild type (Prop1 +/+), Prop1 mutants (Prop1df/df), wild type (Pit1+/+) and Pit1 mutants (Pit1 dw/dw) mice were generated by deep sequencing, in triplicates.
PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells.
Specimen part, Cell line, Subject
View SamplesThe objective is to quantify the contribution of genetic and common environmental effects in the familial resemblances of whole blood genome-wide gene expression levels. We also make comparisons with familial resemblances in blood leukocytes genome-wide DNA methylation levels in the same cohort in order to further investigate biological mechanims.
Familial resemblances in human whole blood transcriptome.
Sex, Specimen part
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