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GSE43881
Homo sapiens
5 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The androgen receptor (AR) is a mediator of both androgen-dependent and castration- resistant prostate cancers. Identification of cellular factors affecting AR transcriptional activity could in principle yield new targets that reduce AR activity and combat prostate cancer, yet a comprehensive analysis of the genes required for AR-dependent transcriptional activity has not been determined. Using an unbiased genetic approach that takes advantage of the evolutionary conservation of AR signaling, we have conducted a genome-wide RNAi screen in Drosophila cells for genes required for AR transcriptional activity and applied the results to human prostate cancer cells. We identified 45 AR-regulators, which include known pathway components and genes with functions not previously linked to AR regulation, such as HIPK2 (a protein kinase) and MED19 (a subunit of the Mediator complex). Depletion of HIPK2 and MED19 in human prostate cancer cells decreased AR target gene expression and, importantly, reduced the proliferation of androgen-dependent and castration-resistant prostate cancer cells. We also systematically analyzed additional Mediator subunits and uncovered a small subset of Mediator subunits that interpret AR signaling and affect AR-dependent transcription and prostate cancer cell proliferation. Importantly, targeting of HIPK2 by an FDA approved kinase inhibitor phenocopied the effect of depletion by RNAi and reduced the growth of AR-positive, but not AR negative, treatment-resistant prostate cancer cells. Thus, our screen has yielded new AR regulators including drugable targets that reduce the proliferation of castration-resistant prostate cancer cells.
Publication Title
A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
The unique metabolic profile of most cancers (aerobic glycolysis) might confer apoptosis-resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential and low expression of the K+ channel Kv1.5, both contributing to apoptosis-resistance. Dichloroacetate (DCA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases mitochondrial membrane potential, increases mitochondrial-H2O2 and activates Kv channels in all cancer, but not normal cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation and tumor growth in vitro and in vivo, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a novel selective anticancer agent.
Publication Title
A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We introduce a family of multivalent peptidomimetic conjugates that modulate the activity of the androgen receptor (AR). Bioactive ethisterone ligands were conjugated to a set of sequence-specific peptoid oligomers. Certain multivalent peptoid conjugates enhance AR-mediated transcriptional activation. We identify a linear and a cyclic conjugate that exhibit potent anti-proliferative activity in LNCaP-abl cells, a model of therapy-resistant prostate cancer. The linear conjugate blocks AR action by competing for ligand binding. In contrast, the cyclic conjugate is active despite its inability to compete against endogenous ligand for binding to AR in vitro, suggesting a non-competitive mode of action. These results establish a versatile platform to design competitive and non-competitive AR modulators with potential therapeutic significance.
Publication Title
Androgen receptor antagonism by divalent ethisterone conjugates in castrate-resistant prostate cancer cells.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 134 Downloadable Samples
Illumina HiSeq 2500, Illumina Genome Analyzer IIx, Illumina HiSeq 2000
Description
Transcriptional regulatory networks (TRNs) provide insight into cellular behavior by describing interactions between transcription factors (TFs) and their gene targets. The Assay for Transposase Accessible Chromatin (ATAC)-seq, coupled with transcription-factor motif analysis, provides indirect evidence of chromatin binding for hundreds of TFs genome-wide. Here, we propose methods for TRN inference in a mammalian setting, using ATAC-seq data to influence gene expression modeling. We rigorously test our methods in the context of T Helper Cell Type 17 (Th17) differentiation, generating new ATAC-seq data to complement existing Th17 genomic resources (plentiful gene expression data, TF knock-outs and ChIP-seq experiments). In this resource-rich mammalian setting our extensive benchmarking provides quantitative, genome-scale evaluation of TRN inference combining ATAC-seq and RNA-seq data. We refine and extend our previous Th17 TRN, using our new TRN inference methods to integrate all Th17 data (gene expression, ATAC-seq, TF KO, ChIP-seq). We highlight new roles for individual TFs and groups of TFs (“TF-TF modules”) in Th17 gene regulation. Given the popularity of ATAC-seq (a widely adapted protocol with high resolution and low sample input requirements), we anticipate that application of our methods will improve TRN inference in new mammalian systems and be of particular use for rare, uncharacterized cell types. Overall design: Gene expression (RNA-seq) of naive and Th17- and Th0-polarized CD4 T Cells
Publication Title
Leveraging chromatin accessibility for transcriptional regulatory network inference in T Helper 17 Cells.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 43 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Analysis of TH17 cells redirected with chimeric antigen receptors (CAR) expressing various signaling domains (including CD28, 4-1BB and ICOS) after surrogate antigen stimulation.
Publication Title
ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells.
Sample Metadata Fields
Specimen part, Time
View Samples- Mus musculus
- 33 Downloadable Samples
- Illumina HiSeq 2000
Description
We report that in developing B cells individual enhancers of Igk make up super-enhancer cluster where contacts between its components rely on all constituents. Reduction of interaction frequency in enhancer knock-out cells is associated with deminished transcriptional output of enhancers and Igk locus. Moreover, we find that Igk enhancer MiEk has an effect on levels of CBFb enrichment on Tcrb enhancer, Eb afffecting Tcrb recombination and T cell development. Overall design: Examination of expression, chromatin accessibility, histone modifications and nuclear organization in developing wild-type and Igk and Tcrb enhancer deficient B and T lymphocytes.
Publication Title
Active and Inactive Enhancers Cooperate to Exert Localized and Long-Range Control of Gene Regulation.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 28 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Unperturbed cholesterol homeostasis is important for normal development and sexual maturation in mice. Cyp51 is the rate limiting step in the post-lanosteorl part of cholesterol biosynthesis. Unlike the full body knockout, hepatocyte specific Cyp51 knockout mice survive throughout adulthood, however their livers are severly affected. Several of the hepatocyte specific Cyp51 knockout mice develop severe liver injury or die prior to reaching adulthood (from 4-10 weeks of age; designated as runts). We aim to uncover the timing and the mechanistic background governing the liver damage and sex differences.
Publication Title
Disrupting Hepatocyte Cyp51 from Cholesterol Synthesis Leads to Progressive Liver Injury in the Developing Mouse and Decreases RORC Signalling.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina Genome Analyzer II
Description
Here we describe microRNA profiling of a single differentiation pathway from the stem cell through to terminally differentated mature cells. Overall design: Populations corresponding to distinct stages in T lymphocyte development, from the hematopoietic stem cell-enriched Lin-Sca+Kit+ population through to mature CD4+ and CD8+ T cells were FACS-sorted to purity from the bone marrow and thymus of C57BL/6 mice. Total RNA was extract from each population from which microRNA sequencing libraries were constructed.
Publication Title
Dynamic microRNA gene transcription and processing during T cell development.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
Purpose: The goals of this study are to compare in vitro polarized T helper 17 cell transcriptome profiling (RNA-seq) in the presence or absence of recombinant murine SAA1 Methods: Th17 mRNA profiles of 96hrs in vitro cultured T helper 17 cells treated with vehicle or recombinant murine SAA1 were generated by deep sequencing, using Illumina RapidRun. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: Burrows–Wheeler Aligner (BWA) and TopHat followed by CuffDiff. qRT–PCR validation was performed using SYBR Green assays. Results: 177 genes were changed more than 2 folds in the presence of recombinant murine SAA1. Conclusions: Our study suggest that SAA1 could augment subset of Th17 transcription program in vitro. Overall design: mRNA profiles of 48hr in vitro cultured Th17 from wild type (WT) mice were generated by deep sequencing using Illumina RapidRun.
Publication Title
An IL-23R/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
- Illumina Genome Analyzer II
Description
Here we show the microRNA genes can been very large and displaying many summarizing structural characteristics Overall design: MicroRNA biogenesis was ablated in CD4+ and CD8+ by deleted Rnasen gene (encoding Drosha). Poly A RNAs were extracted and analyzed by ultra high throughput sequencing
Publication Title
Dynamic microRNA gene transcription and processing during T cell development.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples