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SRP141379
Homo sapiens
126 Downloadable Samples
Illumina HiSeq 2500
Description
CC-671 has been identified as an inhibitor of Cdc2-like kinase 2 (CLK2) and TTK in direct enzyme assays. CLK2 is a member of the CLK family that phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex as part of a regulatory mechanism for control of pre-mRNA splicing. SR proteins are a family of small nuclear ribonucleoprotein particle (snRNP) splicing factors involved in constitutive and alternative splicing. Monitoring specific phospho-biomarkers of CLK2 demonstrated that CC-671 inhibited phosphorylation of CLK2 substrates in cancer cells with mean IC50 of 549 nM in the triple negative breast cancer (TNBC) line CAL51. In this study, RNA sequencing approach was used to quantify the impact of CC-671 treatment on gene transcription and global alternative splicing in CAL51 cells. Differential exon usage analysis demonstrated that CC-671 changed alternative splicing of many genes. In addition, different sets of genes are impacted by CC-671 at both the alternative splicing and mRNA expression. Genes impacted by alternative splicing shared a set of common pathways with genes altered by mRNA expression. This result indicates that CC-671 regulates transcription via both gene expression and alternative splicing mechanisms. Overall design: Triple negative breast cancer (TNBC) line CAL51 was grown in DMEM medium containing 10% fetal bovine serum, as recommended by vendor. The growing cells were treated by CC-671 in three biological replicates at the following concentrations and time intervals. The treatment time points were 6 hour and 24 hour. Concentration of compounds used was 3 and 10 uM. Six million cells from each treatment were harvested and RNA was isolated by RNeasy kit. Poly-A selection and strand-specific RNA library construction were performed, followed by multiplexing indexed libraries and sequencing on the HiSeq 2500 with 2x100 bp read lengths. A total of 16 samples were included in this experiment, including 4 treatment groups with three biological replicates and 2 vehicle control groups with two biological replicates
Publication Title
Synthetic Lethal Strategy Identifies a Potent and Selective TTK and CLK1/2 Inhibitor for Treatment of Triple-Negative Breast Cancer with a Compromised G<sub>1</sub>-S Checkpoint.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 14 Downloadable Samples
Affymetrix Human Genome U95 Version 2 Array (hgu95av2)
Description
Vitiligo Blood Transcriptomics Provides New Insights into Disease Mechanisms and Identifies Potential Novel Therapeutic Targets Abstract Background: Significant gaps remain regarding the pathomechanisms underlying the autoimmune response in vitiligo (VL), where the loss of self-tolerance leads to the targeted killing of melanocytes. Specifically, there is incomplete information regarding alterations in the systemic environment that are relevant to the disease state. Methods: We undertook a genome-wide profiling approach to examine gene expression in the peripheral blood of VL patients and healthy controls in the context of our previously published VL-skin gene expression profile. We used several in silico bioinformatics-based analyses to provide new insights into disease mechanisms and suggest novel targets for future therapy. Results: Unsupervised clustering methods of the VL-blood dataset demonstrate a disease-state-specific set of co-expressed genes. Ontology enrichment analysis of 99 differentially expressed genes (DEGs) uncovers a down-regulated immune/inflammatory response, B-Cell antigen receptor (BCR) pathways, apoptosis and catabolic processes in VL-blood. There is evidence for both type I and II interferon (IFN) playing a role in VL pathogenesis. We used interactome analysis to identify several key blood associated transcriptional factors (TFs) from within (STAT1, STAT6 and NF-kB), as well as hidden (CREB1, MYC, IRF4, IRF1, and TP53) from the dataset that potentially affect disease pathogenesis. The TFs overlap with our reported lesional-skin transcriptional circuitry, underscoring their potential importance to the disease. We also identify a shared VL-blood and -skin transcriptional hot spot that maps to chromosome 6, and includes three VL-blood dysregulated genes (PSMB8, PSMB9 and TAP1) described as potential VL-associated genetic susceptibility loci. Finally, we provide bioinformatics-based support for prioritizing dysregulated genes in VL-blood or skin as potential therapeutic targets. Conclusions: We examined the VL-blood transcriptome in context with our (previously published) VL-skin transcriptional profile to address a major gap in knowledge regarding the systemic changes underlying skin-specific manifestation of vitiligo. Several transcriptional hot spots observed in both environments offer prioritized targets for identifying disease risk genes. Finally, within the transcriptional framework of VL, we identify five novel molecules (STAT1, PRKCD, PTPN6, MYC and FGFR2) that lend themselves to being targeted by drugs for future potential VL-therapy.
Publication Title
Vitiligo blood transcriptomics provides new insights into disease mechanisms and identifies potential novel therapeutic targets.
Sample Metadata Fields
Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Colorectal cancer cells with TP53 mutation are highly resistant to chemotherapeutics. In order to identify potential chemo-resistance signatures, here; we explored the global gene expression profiles of drug resistant colorectal cancer cell line SW480 upon Floxuridine (FdUrd) treatment using Illumina Human HT-12 v4.0 Expression Beadchip Array. Further, significantly altered genes were subjected to the pathway analysis in GeneCodis3 and crucial signaling pathways were found to be enriched. Upon further functional validations, these pathways could be targeted to enhance therapy in human cancers harboring mutant p53.
Publication Title
Transcriptome profiling identifies genes and pathways deregulated upon floxuridine treatment in colorectal cancer cells harboring GOF mutant p53.
Sample Metadata Fields
Sex, Age, Specimen part, Cell line, Treatment
View Samples- Mus musculus
- 4 Downloadable Samples
- Illumina HiSeq 1500
Description
We recently demonstrated that Msx genes, which encode muscle segment homeobox (Msh) transcription factors, regulate the transition of the luminal epithelium from high to low apicobasal polarity that is critical for implantation. In Msx deficient uteri (Msx1d/d/Msx2d/d), apicobasal polarity remains high and implantation fails to occur. However, information on the underlying molecular mechanism of Msx-dependent regulation of epithelial polarity, and the nature of epithelial-mesenchymal interactions that are characteristic of Msx genes, remain limited. In this study, we analyzed gene expression by RNA-sequencing in the luminal epithelium and stroma isolated by laser capture microdissection (LCM) on day 4 of pseudopregnancy in Msx1f/f/Msx2f/f and Msx1d/d/Msx2d/d uteri. We found upregulation of extracellular matrix components in the stroma and downregulation of immunity-related genes in both the luminal epithelium and stroma isolated from Msx1d/d/Msx2d/d mice. In addition, tight junction protein Claudin 1 and small proline-rich protein (Sprr2) were substantially upregulated in Msx1d/d/Msx2d/d epithelia. Overall design: mRNA profiles of luminal epithelium and stroma from a wildtype Msx1f/f/Msx2f/f and a uterine-specific knockout Msx1d/d/Msx2d/d mouse were asessed by RNA-sequencing with the Illumina HiSeq 1500 system
Publication Title
Uterine inactivation of muscle segment homeobox (Msx) genes alters epithelial cell junction proteins during embryo implantation.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
4T1 mouse mammary carcinoma cells have an autocrine FGFR active loop leading to constitutive activation of downstream signaling pathways. We found that FGFR inhibitors have a strong effect on the proliferation and survival of these cells.
Publication Title
Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
4T1 mouse mammary carcinoma cells have an autocrine FGFR active loop leading to constitutive activation of downstream signaling pathways. We found that FGFR inhibitors have a strong effect on 4T1 tumors in-vivo.
Publication Title
Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 42 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Hox genes are key regulators of development. In mammals, the study of these genes is greatly confounded by their large number, overlapping functions, and their interspersed shared enhancers. In this report, we describe a novel recombineering strategy that was used to introduce simultaneous frameshift mutations into the flanking Hoxa9, Hoxa10, and Hoxa11 genes, as well as their paralogs on the HoxD cluster. The resulting mutant mice displayed dramatic homeotic transformations of the reproductive tracts, with uterus anteriorized towards oviduct and the vas deferens anteriorized towards epididymis. The Hoxa9,10,11 mutant mice provided a sensitized genetic background that allowed the discovery of Hoxd9,10,11 reproductive tract patterning function. Both shared and distinct Hox functions were defined. The HoxD genes played a crucial role in the regulation of the uterine immune function. Non-coding nonpolyadenylated RNAs were among the key Hox targets. In addition, we observed a surprising anti-dogmatic posteriorization of the uterine epithelium.
Publication Title
Recombineering-based dissection of flanking and paralogous Hox gene functions in mouse reproductive tracts.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 14 Downloadable Samples
- Illumina HiSeq 2500
Description
Our study demonstrates that neutrophils infiltrate early-stage PTEN-deficient uterine tumors and oppose tumor growth and malignant progression by inducing detachment and ultimately promoting cell death of tumor cells. This RNA-seq study examined the expression profiles of these uterine epithelial tumor cells in the presence versus absence of neutrophil infiltration. Overall design: Tumor cells from 4-week-old tumor-bearing neutrophil-sufficient versus -deficient mice were isolated by fluorescence activated cell sorting, RNA was isolated, and expression profiles were analyzed by deep sequencing.
Publication Title
Neutrophils Oppose Uterine Epithelial Carcinogenesis via Debridement of Hypoxic Tumor Cells.
Sample Metadata Fields
Age, Specimen part, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 2000
Description
Hox genes are key regulators of development. In mammals, the study of these genes is greatly confounded by their large number, overlapping functions, and their interspersed shared enhancers. In this report, we describe a novel recombineering strategy that was used to introduce simultaneous frameshift mutations into the flanking Hoxa9, Hoxa10, and Hoxa11 genes, as well as their paralogs on the HoxD cluster. The resulting mutant mice displayed dramatic homeotic transformations of the reproductive tracts, with uterus anteriorized towards oviduct and the vas deferens anteriorized towards epididymis. The Hoxa9,10,11 mutant mice provided a sensitized genetic background that allowed the discovery of Hoxd9,10,11 reproductive tract patterning function. Both shared and distinct Hox functions were defined. The HoxD genes played a crucial role in the regulation of the uterine immune function. Non-coding nonpolyadenylated RNAs were among the key Hox targets. In addition we observed a surprising anti-dogmatic posteriorization of the uterine epithelium. Overall design: Reproductive tracts were collected from WT and Hox mutant mice (n=3/genotype) aged 3-7 months in order to characterize the molecular changes caused by mutation of Hoxa9,10,11 and Hoxd9,10,11. Female mice were staged and collected in diestrus.
Publication Title
Recombineering-based dissection of flanking and paralogous Hox gene functions in mouse reproductive tracts.
Sample Metadata Fields
Specimen part, Subject
View Samples