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SRP169118
Danio rerio
24 Downloadable Samples
Illumina HiSeq 2500
Description
Glucocorticoid drugs are widely used to treat immune-related diseases, but their use is limited by side effects and by resistance, which especially occurs in macrophage-dominated diseases. In order to improve glucocorticoid therapies, more research is required into the mechanisms of glucocorticoid action. In the present study, we have used a zebrafish model for inflammation to study glucocorticoid effects on the innate immune response. In zebrafish larvae, the migration of neutrophils towards a site of injury is inhibited by the synthetic glucocorticoid beclomethasone, while migration of macrophages is glucocorticoid resistant. RNA sequencing was done on on Fluorescence-Activated Cell Sorting (FACS)-sorted macrophages.The results show that the vast majority of the wounding-induced transcriptional changes in these cells are inhibited by beclomethasone, whereas a small subset is glucocorticoid-insensitive. As a result, beclomethasone decreases the number of macrophages that differentiate towards a pro-inflammatory (M1) phenotype, which we demonstrated using a tnfa:eGFP-F reporter line and analysis of macrophage morphology. We conclude that the glucocorticoid resistance of the wounding-induced macrophage migration is due to the insensitivity of the induction of macrophage-specific chemoattractants to glucocorticoid inhibition, which may explain the relative resistance of macrophage-dominated diseases to glucocorticoid therapy. However, the induction of pro-inflammatory genes in macrophages is strongly attenuated, which inhibits their differentiation to an M1 phenotype. Overall design: After anesthesia with 0.02% aminobenzoic acid ethyl ester (tricaine, Sigma Aldrich), the tails of 3 days post fertilization (dpf) embryos were partially amputated with a 1mm sapphire blade (World Precision Instruments) on 2% agarose-coated Petri dishes under a Leica M165C stereomicroscope (Chatzopoulou et al., 2016). Amputated and non-amputated (control) embryos were pretreated for 2 hours with 25 µM beclomethasone (Sigma Aldrich) or vehicle (0.05% dimethyl sulfoxide (DMSO)) in egg water prior to amputation and received the same treatment after the amputation. Macrophages were sorted from Tg(mpeg1.4:mCherry-F) embryos as previously described (Rougeot et al., 2014; Zakrzewska et al., 2010) at 4 hours post amputation (hpa). The sorted cells were collected in QIAzol lysis reagent (Qiagen) for RNA isolation. Extracted total RNA was amplified using the SMART-seq V4 kit (Clontech) for sequencing. The RNA seq libraries generated with the SMART-seq V4 kit were sequenced using an Illumina HiSeq 2500 instrument according to the manufacturer's instructions with a read length of 50 nucleotides.
Publication Title
Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration.
Sample Metadata Fields
Treatment, Subject
View Samples- Homo sapiens
- 6 Downloadable Samples
Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Identification of genes that are involved in self-seeding by comparing gene expression profiles between parental MDA-MB-231 cells and seeder cells (MDA-231-S1a and S1b)
Publication Title
Tumor self-seeding by circulating cancer cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 27 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
In advanced malignancies, cancer cells have acquired capabilities to resist a variety of stress-inducing insults. We show that c-Jun N-terminal kinase (JNK) stress signaling is highly active in cancer cells from patients with late stage breast cancer and promotes tumor growth and metastasis in mouse models. Transcriptomic analysis revealed that JNK activity induces genes associated with extracellular matrix (ECM), wound healing and mammary stem cells. The ECM proteins and niche components osteopontin (SPP1) and tenascin C (TNC) are induced by JNK signaling and promote metastatic colonization of the lungs. Notably, treatment with chemotherapeutic drugs induces JNK activity in breast cancer cells, reinforcing the production of SPP1 and TNC. Inhibition of JNK or reduction of SPP1 or TNC expression sensitizes primary tumors and metastases in mice to chemotherapy.
Publication Title
Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
In advanced malignancies, cancer cells have acquired capabilities to resist a variety of stress-inducing insults. We show that c-Jun N-terminal kinase (JNK) stress signaling is highly active in cancer cells from patients with late stage breast cancer and promotes tumor growth and metastasis in mouse models. Transcriptomic analysis revealed that JNK activity induces genes associated with extracellular matrix (ECM), wound healing and mammary stem cells. The ECM proteins and niche components osteopontin (SPP1) and tenascin C (TNC) are induced by JNK signaling and promote metastatic colonization of the lungs. Notably, treatment with chemotherapeutic drugs induces JNK activity in breast cancer cells, reinforcing the production of SPP1 and TNC. Inhibition of JNK or reduction of SPP1 or TNC expression sensitizes primary tumors and metastases in mice to chemotherapy.
Publication Title
Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
In advanced malignancies, cancer cells have acquired capabilities to resist a variety of stress-inducing insults. We show that c-Jun N-terminal kinase (JNK) stress signaling is highly active in cancer cells from patients with late stage breast cancer and promotes tumor growth and metastasis in mouse models. Transcriptomic analysis revealed that JNK activity induces genes associated with extracellular matrix (ECM), wound healing and mammary stem cells. The ECM proteins and niche components osteopontin (SPP1) and tenascin C (TNC) are induced by JNK signaling and promote metastatic colonization of the lungs. Notably, treatment with chemotherapeutic drugs induces JNK activity in breast cancer cells, reinforcing the production of SPP1 and TNC. Inhibition of JNK or reduction of SPP1 or TNC expression sensitizes primary tumors and metastases in mice to chemotherapy.
Publication Title
Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Rattus norvegicus
- 19 Downloadable Samples
- Affymetrix Rat Gene 1.0 ST Array (ragene10st)
Description
Maternal immune activation is a risk factor for the development of schizophrenia and autism. Infections during pregnancy activate the mother's immune system and alter the fetal environment with sub-sequence effects of CNS function and behavior in the offspring, but the cellular and molecular links between infection-induced altered fetal development and risk for neuropsychiatric disorders are unknown. We investigated the immunological, molecular, and behavioral effects of MIA in the offspring of pregnant Sprague-Dawley rats given an intraperitoneal (0.25 mg/kg) injection of lipopolysaccharide (LPS) on embryonic day 15. LPS significantly elevated pro-inflammatory cytokines in maternal serum, amniotic fluid, and fetal brain at 4 h, and levels decreased but remained elevated at 24 h. Offspring born to LPS-dams exhibited reduced social and exploration behaviors as juveniles and young adults. Whole genome microarray analysis of the fetal brain at 4 h post maternal LPS was performed to elucidate possible molecular mechanisms by which MIA effects the fetal brain. We observed dysregulation of 3,285 genes in restricted functional categories, with increased mRNA expression of cellular stress and cell death genes and reduced expression of developmentally-regulated and brain-specific genes, specifically those that regulate neuronal migration of GABAergic interneurons.
Publication Title
Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 19 Downloadable Samples
- Illumina HiSeq 2000
Description
How G4C2 repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. Here, we report the first mouse model to express poly(PR), a dipeptide repeat protein synthesized from expanded G4C2 repeats. Expression of GFP-(PR)50 throughout the mouse brain yielded progressive brain atrophy, neuron5 loss, loss of poly(PR)-positive cells and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused abnormal histone methylation, lamin invaginations, decreases in HP1a expression, and disruptions of HP1a liquid phases. These aberrations of histone methylation, lamins and HP1a, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element10 expression and double-stranded RNA accumulation. Thus, we uncover new mechanisms by which poly(PR) contributes to c9FTD/ALS pathogenesis. Overall design: Examination of transcriptome profiles using RNA-seq on 3 month old mice expressing PR and GR polypetides with an AAV expression vector. The Poly(PR) analysis consisted of 7 mice expressing AAV-GFP-(PR)50 and 4 AAV-GFP harvest-matched controls. The Poly(GR) analysis consisted of 4 mice expressing AAV-GFP-(GR)100 and 4 AAV-GFP harvest-matched controls.
Publication Title
Heterochromatin anomalies and double-stranded RNA accumulation underlie <i>C9orf72</i> poly(PR) toxicity.
Sample Metadata Fields
Sex, Age, Cell line, Subject
View Samples- Homo sapiens
- 36 Downloadable Samples
- Illumina HiSeq 2500
Description
We discovered a rare missense mutation in NR1H4 (R436H), which encodes the farnesoid X receptor (FXR), associating with lower levels of total cholesterol in the Icelandic population. To explore the effects of R436H we used CRISPR-Cas9 to generate homozygous NR1H4 R436H and NR1H4 knockout human iPSC lines which we differentiated to hepatocytes. Hepatocytes were treated with an FXR agonist for 24 hours and transcript abundance measured by RNA-seq. The global response to FXR activation in NR1H4 R436H cells was very similar to that of wild-type cells showing that it is not a loss-of-function mutation. However, we did observe subtle gene expression differences compatible with an effect on lipids when we compared R436H agonist treated hepatocytes to wild-type agonist treated hepatocytes. Overall design: RNA-seq was performed on wild-type, NR1H4 knockout and NR1H4 R436H iPSC-derived hepatocytes treated with FXR agonist GW4064.
Publication Title
Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Mus musculus
- 768 Downloadable Samples
- Illumina HiSeq 2000
Description
This study was conducted to determine heterogeneity of cancer-associated fibroblasts (CAFs) in mammary tumors, by unsupervised analysis of single cell transcriptomes. Overall design: 768 single EpCAM-, CD45-, CD31- NG2- fibroblasts were isolated from mammary tumors of two 14 week old MMTV-PyMT mice. The cells were sequenced following the Smart-Seq2 protocol (Picelli et al. Nature Methods 2013).
Publication Title
Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing.
Sample Metadata Fields
Age, Specimen part, Cell line, Subject
View Samples