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SRP070840
Homo sapiens
48 Downloadable Samples
IlluminaHiSeq2500
Description
We performed a genome-scale CRISPR screen in a KRAS-mutant pancreatic cancer cell line treated with the MEK inhibitor trametinib, and found that loss of the transcriptional repressor CIC confers resistance to MEK inhibition. We determined that CIC loss also confers resistance to MEK or BRAF inhibition in lung cancer, colorectal cancer, and melanoma cell lines with mutant RAS or BRAF. CIC is a transcriptional repressor that is phosphorylated and inhibited by the MAPK pathway. We hypothesized that inhibition of the MAPK pathway would lead to activation of CIC and repression of CIC target genes. Loss of CIC would therefore restore expression of these genes, conferring drug resistance. To identify the relevant CIC target genes that mediate trametinib resistace, we generated 4 Cas9-expressing cell lines from different lineages and with different RAS or RAF mutations, and generated control (gGFP) or CIC-knockout (gCIC) cell lines. We treated cells with DMSO or trametinib for 24 hours, and performed NRA-seq. We found that trametinib treatment reduces expression of at least one member of the PEA3 family of ETS transcription factors (ETV1, ETV4, and ETV5) in all cell lines assessed, and that loss of CIC results in maintained expression of these genes despite MEK inhibition. We further validated that ETV1, 4, and 5 expression was necessary for resistance mediated by CIC loss; and that ETV1, 4, or 5 expression was sufficient to confer trametinib resistance. Overall design: 4 Cas9-expressing human cancer cell lines (A549, CALU1, HCT116, PATU8902) were used to generate 3 isogenic cell lines with intact CIC (gGFP-1) or knocked out CIC (gCIC-1 or gCIC-2). Each of these 12 cell lines were treated with DMSO or trametinib for 24 hours (duplicates)
Publication Title
ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 39 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
LNCaP-derived MDV3100-resistant clones were treated with MDV3100 for 24h prior to collection
Publication Title
An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide).
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 13 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Genetically engineered LNCaPs overexpressing various AR alleles were treated with 0.1% DMSO or 10uM MDV3100 for 24h prior to collection
Publication Title
An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide).
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 16 Downloadable Samples
- Illumina HiSeq 2500
Description
To examine molecular mechanisms of aortic valve stenosis in mice with hypertension and hypercholesterolemia, RNA-Seq was used during the developmental phase of stenosis to identify new gene targets. Overall design: Four groups of mice were studied: controls (CON), hypertensive (HT), hypercholesterolemic (HC), and HC/HT. Transgenic mice overexpressing human renin and human angiotensinogen served as the HT model and ApoE knockout mice served as the HC model. A sample size of N=4 was used for each of the four groups.
Publication Title
Fibrotic Aortic Valve Stenosis in Hypercholesterolemic/Hypertensive Mice.
Sample Metadata Fields
No sample metadata fields
View Samples- Caenorhabditis elegans
- 47 Downloadable Samples
- Affymetrix C. elegans Genome Array (celegans)
Description
Transgenic animals were engineered to express human amyloid peptide controlled by a muscle-specific, heat-inducible promoter. At low temperatures (16C) Abeta expression is minimal, while at higher temperatures (20-25C) Abeta accummulates in large quantities and causes paralysis.
Publication Title
Identifying Aβ-specific pathogenic mechanisms using a nematode model of Alzheimer's disease.
Sample Metadata Fields
Time
View Samples- Mus musculus
- 54 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The Melanoma-associated Antigen gene family (MAGE) generally encodes for tumour antigens. We recently have identified one of the MAGE gene members, Mageb16 to be highly expressed in undifferentiated murine embryonic stem cells (mESCs). The role of Mageb16 for the differentiation of the pluripotent stem cells is completely unknown. Here we demonstrate that Mageb16 (41 kDa) is distributed in cytosol and/or in surface membrane in undifferentiated mESCs. A transcriptome study was performed with differentiated short hairpin RNA (shRNA)-mediated Mageb16 knockdown (KD ESCs) and scrambled control (SCR) ESCs until a period of 22 days. Mageb16 KD ESCs mainly differentiated towards mesodermal derivatives such as cardiovascular lineages. Mesoderm-oriented differentiation initiated biological processes such as adipogenesis, osteogenesis, limb morphogenesis and spermatogenesis were significantly enriched in the differentiated Mageb16 KD ESCs. Cardiomyogenesis in differentiated KD mESCs was stronger when compared to differentiated SCR and wild mESCs. The expression of non-coding RNA (ncRNA) Lin28a and other epigenetic regulatory genes, nucleocytoplasmic trafficking and genes participating in spermatogenesis have also declined faster in the differentiating Mageb16 KD ESCs. We conclude that Mageb16 plays a crucial role for differentiation of ESCs, specifically to the mesodermal lineages. Regulative epigenetic networks and nucleocytoplasmic modifications induced by Mageb16 may play a role for the critical role of Mageb16 for the ESCs differentiation.
Publication Title
Depletion of Mageb16 induces differentiation of pluripotent stem cells predominantly into mesodermal derivatives.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 32 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
ICU acquired weakness (ICUAW) is a complication of critical illness characterized by structural and functional impairment of skeletal muscle that may persist for years after ICU discharge with many survivors developing protracted courses with few regaining functional independence. Elucidating molecular mechanisms underscoring sustained ICUAW is crucial to understanding outcomes linked to different morbidity trajectories as well as for the development of novel therapies. Quadriceps muscle biopsies and functional measures of muscle strength and mass were obtained at 7 days and 6 months post-ICU discharge from a cohort of ICUAW patients. Unsupervised co-expression network analysis of transcriptomic profiles identified discrete modules of co-expressed genes associated with the degree of muscle weakness and atrophy in early and sustained ICUAW. Modules were enriched for genes involved in skeletal muscle regeneration and extracellular matrix deposition. Collagen deposition in persistent ICUAW was confirmed by histochemical stain. Modules were further validated in an independent cohort of critically ill patients with sepsis-induced multi-organ failure and a porcine model of ICUAW, demonstrating disease-associated conservation across species and peripheral muscle type. Our findings provide a pathomolecular basis for sustained ICUAW, implicating aberrant expression of distinct skeletal muscle structural and regenerative genes in early and persistent ICUAW.
Publication Title
Transcriptomic analysis reveals abnormal muscle repair and remodeling in survivors of critical illness with sustained weakness.
Sample Metadata Fields
Sex, Age
View Samples- Drosophila melanogaster
- 6 Downloadable Samples
- Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Pausing of RNA polymerase II disrupts DNA-specified nucleosome organization to enable precise gene regulation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 9 Downloadable Samples
- Illumina MouseWG-6 v2.0 expression beadchip
Description
Comparative analysis of Endodermal-like cell lines with demonstrated ability to support myocardial differentiation
Publication Title
A comparative analysis of extra-embryonic endoderm cell lines.
Sample Metadata Fields
Specimen part
View Samples- Drosophila melanogaster
- 6 Downloadable Samples
- Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
Metazoan transcription is controlled through either coordinated recruitment of transcription machinery to the gene promoter, or subsequently, through regulated pausing of RNA polymerase II (Pol II) in early elongation. We report that a key difference between genes that use these distinct regulatory strategies lies in the chromatin architecture specified by their DNA sequences. Pol II pausing is prominent at highly-regulated genes whose sequences inherently disfavor nucleosome formation within the gene, but favor nucleosomal occlusion of the promoter. Pausing of polymerase maintains these genes in an active state by inhibiting the formation of repressive promoter chromatin. In contrast, promoters of housekeeping genes that lack paused Pol II are deprived of nucleosomes regardless of polymerase binding, but show higher nucleosome occupancy downstream. Our results suggest that the default chromatin state of a gene instructs its regulation, and that highly-regulated promoters have evolved to encourage competition between nucleosomes and paused Pol II for promoter occupancy.
Publication Title
Pausing of RNA polymerase II disrupts DNA-specified nucleosome organization to enable precise gene regulation.
Sample Metadata Fields
Specimen part
View Samples