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SRP159645
Mus musculus
35 Downloadable Samples
Illumina HiSeq 2500
Description
SETD5 gene mutations have been identified as a frequent cause of idiopathic intellectual disability. Here we show that Setd5 haploinsufficient mice present developmental defects such as abnormal brain to body weight ratio and neural crest defect associated phenotypes. Furthermore, Setd5 mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalisation and behavioural inflexibility. Behavioural issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data suggest that Setd5 might regulate RNA polymerase II dynamics and gene transcription during development and learning via its interaction with the Hdac3 and Paf1 complexes. Our results emphasize the decisive role of Setd5 in a biological pathway found to be disrupted in intellectual disability and autism spectrum disorder patients. Overall design: RNA-sequencing for wild type and Setd5 heterozygous knockout mice in two settings. First, in whole embryo samples (age E9.5), three biological replicates each. Second, gene expression changes due to contextual fear conditioning (CFC) was studied by comparing baseline transcription in homecage (HC) mice with transcription one hour (CFC_1h) or three hours (CFC_3h) after fear conditioning (4-5 biological replicates per time point and genotype).
Publication Title
Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to decreased levels of brain BCAAs, abnormal mRNA translation and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function. Overall design: RNA-sequencing of cerebellum from 3 wildtype mice and 3 Slc7a5 KO mice
Publication Title
Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 10 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
To better understand the impact of integrin beta3 signaling in myeloid cells on the tumor microenvironment, we compared the gene expression profiles of FACS isolated GFP+ PyMT-BO1 MFP tumor cells and also M2 TAMs (CD11b+Gr1-F4/80+CD206+) from tumor tissue of WT mice and b3 mice.
Publication Title
Antagonizing Integrin β3 Increases Immunosuppression in Cancer.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 28 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Adaptive resistance to targeted therapy such as BRAF inhibitors represents in melanoma a major drawback to this otherwise powerful treatment. Some of the underlying molecular mechanisms have recently been described: hyperactivation of the BRAF-MAPK pathway, of the AKT pathway, of the TGF/EGFR/PDGFRB pathway, or the low MITF/AXL ratio. Nevertheless, the phenomenon of early resistance is still not clearly understood. In this report, we show that knockdown of neural crest-associated gene ID3 increases the melanoma sensitivity to vemurafenib short-term treatment. In addition, we observe an ID3-mediated regulation of cell migration and of the expression of resistance-associated genes such as SOX10 and MITF. In sum, these data suggest ID3 as a new key actor of melanoma adaptive resistance to vemurafenib and as a potential drug target. Molecular mechanisms that are responsible for the development of human skin epithelial cells are not completely understood so far. As a consequence, the efficiency to establish a pure skin epithelial cell population from human induced pluripotent stem cells (hiPSC) remains poor. Using an approach including RNA interference and high-throughput imaging of early epithelial cells, we could identify candidate kinases which are involved in skin epithelial differentiation. Among them, we found HIPK4 to be an important inhibitor of this process. Indeed, its silencing increased the amount of generated skin epithelial precursors, increased the amount of generated keratinocytes and improved growth and differentiation of organotypic cultures, allowing for the formation of a denser basal layer and stratification with the expression of several keratins. Our data bring substantial input in the regulation of human skin epithelial differentiation and for improving differentiation protocols from pluripotent stem cells.
Publication Title
New role of ID3 in melanoma adaptive drug-resistance.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 308 Downloadable Samples
- Affymetrix Human Gene 1.1 ST Array (hugene11st)
Description
Early diagnosis of transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease modifying therapies. Early diagnosis is often difficult because the patient exhibits apparent symptoms of polyneuropathy or cardiomyopathy, but has a negative amyloid biopsy. Thus, there is a pressing need for more objective, quantitative diagnostics and biomarkers of TTR-aggregation-associated polyneuropathy and cardiomyopathy. This is especially true in the context of clinical trials demonstrating significant disease modifying effects, e.g. when the TTR tetramer stabilizer tafamidis was administered to familial amyloid polyneuropathy (FAP) patients early in the disease course. When asked if the findings of the tafamidis registration trial were sufficiently robust to provide substantial evidence of efficacy for a surrogate endpoint that is reasonably likely to predict a clinical benefit the advisory committee said yes, but the FDA rejected the tetramer stabilization surrogate biomarker required for orphan tafamidis approvalhence, acceptable biomarkers are badly needed. Herein, we explored whether peripheral blood cell mRNA expression profiles could differentiate symptomatic from asymptomatic V30M FAP patients, and if such a profile would normalize upon tafamidis treatment. We demonstrate that blood cell gene expression patterns reveal sex-independent as well as male and female specific inflammatory signatures in symptomatic FAP patients, but not in asymptomatic carriers, that normalize in FAP patients 6 months after tafamidis treatment. Thus these signatures have potential both as an early diagnostic and as a surrogate biomarker for measuring response to treatment in FAP patients.
Publication Title
Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific Signatures.
Sample Metadata Fields
Age, Specimen part
View Samples- Rattus norvegicus
- 36 Downloadable Samples
- Illumina HiSeq 2500
Description
We examined effects of early life stress (ELS) and environmental enrichment (EE) during development on BACHD rat striatal gene expression using RNA sequencing Overall design: We used a 2×3 factorial design with two genotypes (wildtype, WT; transgene, TG) and three environmental conditions (standard environment, SE; enriched environment, EE; early life stress, ELS) to assess effects of environmental enrichment and early life stress on striatal gene expression of 2-month-old WT and BACHD rats
Publication Title
Environment-dependent striatal gene expression in the BACHD rat model for Huntington disease.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Transciptome analysis using a panel of WM793 melanoma cell lines following stable overexpression of wild-type or mutant forms of human NME1
Publication Title
Identification of a gene expression signature associated with the metastasis suppressor function of NME1: prognostic value in human melanoma.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 12 Downloadable Samples
- NextSeq 500
Description
Glucocorticoids (GCs) are essential steroid hormones that regulate the immune system. GCs have been widely used to treat various inflammation disorders and auto-immune diseases, due to their potent immune repression properties. Overall design: HeLa cells were cultured with DMEM plus 10% charcoal-stripped FBS. HeLa cells were treated in the presence of 100 nM triamcinolone acetonide (TA) for 4 hours. Cells were then collected for RNA-seq.
Publication Title
Extensive epigenomic integration of the glucocorticoid response in primary human monocytes and in vitro derived macrophages.
Sample Metadata Fields
Cell line, Treatment, Subject
View Samples- Homo sapiens
- 8 Downloadable Samples
- NextSeq 500
Description
Glucocorticoids (GCs) are essential steroid hormones that regulate the immune system. GCs have been widely used to treat various inflammation disorders and auto-immune diseases, due to their potent immune repression properties. Overall design: Monocytes from healthy donors were cultured in the presence of 100 nM triamcinolone acetonide (TA), 100 nM Dexamethasone (Dex) or 100 nM Prednisolone (Pred) for 4 hours. Cells were then collected for RNA-seq.
Publication Title
Extensive epigenomic integration of the glucocorticoid response in primary human monocytes and in vitro derived macrophages.
Sample Metadata Fields
Specimen part, Disease, Treatment, Subject
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
VAF347 is a low molecular weight compound which inhibits allergic lung inflammation in vivo. This effect is likely due to a block of dendritic cell (DC) function to generate pro-inflammatory T-helper (Th) cells since VAF347 inhibits IL-6, CD86 and HLA-DR expression by human monocyte derived DC, three relevant molecules for Th-cell generation. Here we demonstrate that VAF347 interacts with the aryl hydrocarbon receptor (AhR) protein resulting in activation of the AhR signaling pathway. Functional AhR is responsible for the biological activity of VAF347 since, i) other AhR agonists display an identical activity profile in vitro, ii) gene silencing of wild type AhR expression or forced over-expression of a trans-dominant negative AhR ablates VAF347 activity to inhibit cytokine induced IL-6 expression in a human monocytic cell line and iii) AhR deficient mice are resistant to the compounds ability to block allergic lung inflammation in vivo. These data identify the AhR protein as key molecular target of VAF347 and its essential role for mediating the anti-inflammatory effects of the compound in vitro and in vivo.
Publication Title
Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound.
Sample Metadata Fields
No sample metadata fields
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