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SRP133227
Homo sapiens
13 Downloadable Samples
Illumina HiSeq 2500
Description
BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance, which is frequently caused by reactivation of the Mitogen Activated Protein Kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor (HDACi) vorinostat represses SLC7A11 that leads to a lethal increase in the already elevated levels of ROS in drug-resistant cells, thereby causing selective apoptotic death of only the drug resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with HDACi in mice results in a dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor resistant melanoma, we find that HDACi can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here. Overall design: one replicate of RNA Seq data A375, A375R, A375DR vorinostat treated and patient samples pre- post- vorinostat treatment
Publication Title
An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Cell line, Treatment, Subject
View Samples- Mus musculus
- 30 Downloadable Samples
Affymetrix Mouse Gene 2.1 ST Array (mogene21st)
Description
CNIs drastically modify the Treg specific transcriptional program in vivo in an IL-2 dependent manner
Publication Title
IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 207 Downloadable Samples
- Illumina HiSeq 2000
Description
Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth retardation, feeding problems, and various congenital malformations. Our combined clinical and molecular data define the 'YY1 syndrome' as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from person-derived cells, using antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding, with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators. Overall design: Individuals with mutations or deletion in YY1 were identified among patients with idiopathic intellectual disability. LCLs were established from 4 of these patients (1 deletion, 2 missense mutations, and 1 non-sense mutation undergoing non-sense-mediated decay) as well as from unrelated controls, and their transcriptome were compared.
Publication Title
YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.
Sample Metadata Fields
Specimen part, Subject
View Samples- Arabidopsis thaliana
- 12 Downloadable Samples
- Affymetrix Arabidopsis ATH1 Genome Array (ath1121501)
Description
Genome wide gene expression profile of the lrx1 root hair mutant and the suppressor mutations lrx1 rol1-1 and lrx1 rol1-2.
Publication Title
The Arabidopsis root hair cell wall formation mutant lrx1 is suppressed by mutations in the RHM1 gene encoding a UDP-L-rhamnose synthase.
Sample Metadata Fields
Age, Specimen part
View Samples- Arabidopsis thaliana
- 36 Downloadable Samples
- Affymetrix Arabidopsis ATH1 Genome Array (ath1121501)
Description
The molecular chaperone HSP90 aids the maturation of a diverse but select set of metastable protein clients, many of which are key to a variety of signal transduction pathways. HSP90 function has been best investigated in animal and fungal systems, where inhibition of the chaperone has exceptionally diverse effects, ranging from reversing oncogenic transformation to facilitating the acquisition of drug resistance. Inhibition of HSP90 in the model plant Arabidopsis thaliana uncovers novel morphologies dependent on normally cryptic genetic variation and increases stochastic variation inherent to developmental processes. The biochemical activity of HSP90 is strictly conserved between animals and plants. However, the substrates and pathways dependent on HSP90 in plants are poorly understood. Progress has been impeded by reliance on light-sensitive HSP90 inhibitors due to redundancy in the A. thaliana HSP90 gene family. Here we present phenotypic and genome-wide expression analyses of A. thaliana with constitutively reduced HSP90 levels achieved by RNAi targeting. HSP90 reduction affects a variety of quantitative life-history traits, including flowering time and total seed set, and decreases developmental stability. Further, by quantitative analysis of morphological phenotypes, we demonstrate that HSP90-reduction increases phenotypic diversity in both seedlings and adult plants. Several morphologies are synergistically affected by HSP90 and growth temperature. Genome-wide expression analyses also suggest a central role for HSP90 in the genesis and maintenance of plastic responses. The expression results are substantiated by examination of the response of HSP90-reduced plants to attack by caterpillars of the generalist herbivore Trichoplusia ni. HSP90 reduction potentiates a more robust herbivore defense response. In sum, we propose that HSP90 exerts global effects on the environmental responsiveness of plants to many different stimuli. The comprehensive set of HSP90-reduced lines described here is a vital instrument to further examine the role of HSP90 as a central interface between organism, development, and environment.
Publication Title
Phenotypic diversity and altered environmental plasticity in Arabidopsis thaliana with reduced Hsp90 levels.
Sample Metadata Fields
Age, Specimen part
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Matrix elasticity, replicative senescence and DNA methylation patterns of mesenchymal stem cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Matrix elasticity influences differentiation of mesenchymal stem cells (MSCs) but it is unclear if these effects are only transient - while the cells reside on the substrate - or if they reflect persistent lineage commitment. In this study, MSCs were continuously culture-expanded in parallel either on polydimethylsiloxane (PDMS) gels of different elasticity or on tissue culture plastic (TCP) to compare impact on replicative senescence, in vitro differentiation, gene expression, and DNA methylation (DNAm) profiles. The maximal number of cumulative population doublings was not affected by matrix elasticity. Differentiation towards adipogenic and osteogenic lineage was increased on soft and rigid biomaterials, respectively - but this propensity was no more evident if cells were transferred to TCP. Global gene expression profiles and DNAm profiles revealed relatively few differences in MSCs cultured on soft or rigid matrices. Furthermore, only moderate DNAm changes were observed upon culture on very soft hydrogels of human platelet lysate. Our results support the notion that matrix elasticity influences cellular differentiation while the cells are organized on the substrate, but it does not have major impact on cell-intrinsic lineage determination, replicative senescence or DNAm patterns.
Publication Title
Matrix elasticity, replicative senescence and DNA methylation patterns of mesenchymal stem cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Rattus norvegicus
- 14 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
The intercalated disc of cardiac myocytes is emerging as a crucial structure in the heart. Loss of intercalated disc proteins like N-cadherin causes lethal cardiac abnormalities, mutations in intercalated disc proteins cause human cardiomyopathy. A comprehensive screen for novel mechanisms in failing hearts demonstrated that expression of the lysosomal integral membrane protein-2 (LIMP-2) is increased in cardiac hypertrophy and heart failure in both rat and human myocardium. Complete loss of LIMP-2 in genetically engineered mice did not affect cardiac development; however these LIMP-2 null mice failed to mount a hypertrophic response to increased blood pressure but developed cardiomyopathy. Disturbed cadherin localization in these hearts suggested that LIMP-2 has important functions outside lysosomes. Indeed, we also find LIMP-2 in the intercalated disc, where it associates with cadherin. RNAi-mediated knockdown of LIMP-2 decreases the binding of phosphorylated b-catenin to cadherin, while overexpression of LIMP-2 has the opposite effect. Taken together, our data show that lysosomal integrated membrane protein-2 is crucial to mount the adaptive hypertrophic response to cardiac loading. We demonstrate a novel role for LIMP-2 as an important mediator of the intercalated disc.
Publication Title
Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 10 Downloadable Samples
- IlluminaHiSeq2500
Description
We used NEBNext Ultra Directional RNA Library Prep Kits to prepare RNA-seq libraries of total RNA from hnRNP A2/B1 and A1 depleted A549 cells. Pro-seq libraries were prepared from A549 cells using Illumina adapters Overall design: hnRNP A2/B1 and A1 depleted A549 cells were generated by lentiviral infections of shRNA constructs. RNAs were isolated using Trizol.
Publication Title
A widespread sequence-specific mRNA decay pathway mediated by hnRNPs A1 and A2/B1.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 26 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Cytokine signaling is transmitted by cell surface receptors which function as natural biological switches to control among others mainly immune related processes. Recently, we have designed synthetic cytokine receptors (SyCyRs) consisting of GFP- and mCherry-nanobodies fused to trans-membrane and intracellular domains of cytokine receptors, which phenocopied cytokine signaling induced by non-physiological homo- and heterodimeric GFP-mCherry ligands. Interleukin 22 signals via IL-22Rα1 and the common IL-10R2, belongs to the IL-10 cytokine family and is critically involved in tissue regeneration. IL-22 SyCyRs phenocopied native IL-22 signal transduction as shown by induction of cytokine-dependent cellular proliferation, signal transduction and transcriptome analysis. Whereas homodimeric IL-22Rα1 SyCyRs failed to activate signaling, homodimerization of the second IL-22 signaling chain, SyCyR(IL-10R2), which was considered to not induce signal transduction, lead to induction of signal transduction. Interestingly, the SyCyR(IL-10R2) and SyCyR(IL-22Rα1) were able to form functional heterodimeric receptor signaling complexes with the synthetic IL-6 receptor chain SyCyR(gp130). In summary, we demonstrated that IL-22 signaling can be phenocopied by synthetic cytokine receptors. Further we identified a novel IL-10R2 homodimeric receptor complex and receptor cross-talk with gp130.
Publication Title
Synthetic interleukin 22 (IL-22) signaling reveals biological activity of homodimeric IL-10 receptor 2 and functional cross-talk with the IL-6 receptor gp130.
Sample Metadata Fields
Specimen part, Treatment
View Samples