KMS-11 and KMS-34 cells were exposed to stepwise increasing concentrations of carfilzomib over a period of 18 weeks: cells adapted to growth in 4 nM carfilzomib by 4 weeks, in 6 nM in another 6 weeks and in 12 nM after a further 8 weeks. The resulting cell cultures, denoted KMS-11/Cfz and KMS-34/Cfz, respectively, retained resistance to carfilzomib even when tested after removal of selective pressure for approximately 8 weeks.
KLF4-SQSTM1/p62-associated prosurvival autophagy contributes to carfilzomib resistance in multiple myeloma models.
Specimen part, Cell line
View SamplesLP-1 cells were exposed to stepwise increasing concentrations of carfilzomib over a period of 18 weeks: cells adapted to growth in 4 nM carfilzomib by 4 weeks, in 6 nM in another 6 weeks and in 12 nM after a further 8 weeks. The resulting cell culture, denoted LP-1/Cfz, retained resistance to carfilzomib even when tested after removal of selective pressure for approximately 8 weeks.
Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming.
Cell line
View SamplesHigh fat feeding is deleterious for skeletal muscle metabolism, while exercise has well documented beneficial effects for these same metabolic features. To identify the genomic mechanisms by which exercise ameliorates some of the deleterious effects of high fat feeding, we investigated the transcriptional and epigenetic response of human skeletal muscle to 9 days of a high-fat diet (HFD) alone (Sed-HFD) or in combination with resistance exercise (Ex-HFD), using genome-wide profiling of gene expression (by RNA-seq) and DNA methylation (by Reduced Representation Bisulfite Sequencing). HFD markedly induced expression of immune and inflammatory genes which was not attenuated by Ex. In contract, Ex markedly remodelled expression of genes associated with muscle growth and structure. We detected marked DNA methylation changes following HFD alone and in combination with Ex. Among the genes that showed significant association between DNA methylation changes and gene expression were glycogen phosphorylase, muscle associated (PYGM), which was epigenetically regulated in both groups, and angiopoiten like 4 (ANGPTL4), which was regulated only following Ex. We conclude that Short-term Ex does not prevent HFD-induced inflammatory response, but provokes a genomic response that may preserve skeletal muscle from atrophy. Epigenetic adaptation provides important mechanistic insight into the gene specific regulation of inflammatory and metabolic processes in human skeletal muscle. Overall design: Sedentary or exercising human subjects undergo high-fat diet intervention.
Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans.
Specimen part, Subject, Time
View SamplesMedulloblastoma is the most common form of malignant paediatric brain tumour and is the leading cause of childhood cancer related mortality. The four molecular subgroups of medulloblastoma that have been identified WNT, SHH, Group 3 and Group 4 - have molecular and topographical characteristics suggestive of different cells of origin. Definitive identification of the cell(s) of origin of the medulloblastoma subgroups, particularly the poorer prognosis Group 3 and Group 4 medulloblastoma, is critical to understand the pathogenesis of the disease, and ultimately for the development of more effective treatment options.
Gene expression analyses of the spatio-temporal relationships of human medulloblastoma subgroups during early human neurogenesis.
Sex, Age
View SamplesInhibiting tafazzin a cardiolipin remodeling enzyme reduces stemness of AML by modulating the level of phosphatidylserine Overall design: Gene expression analysis upon knock-down of TAZ by two independent shRNAs
The Mitochondrial Transacylase, Tafazzin, Regulates for AML Stemness by Modulating Intracellular Levels of Phospholipids.
Specimen part, Cell line, Subject
View SamplesThe goal of this work was to identify all estrogen receptor beta target genes using RNA sequencing in MDA-MB-468 triple negative breast cancer cells engineered with inducible expression of full length estrogen receptor beta. Overall design: MDA-MB-468 breast cancer cells with inducible ERb expression (MDA-468-ERb cells) were treated in triplicate with vehicle (control, no ERb) or doxycycline (plus ERb) for 48 hr prior to treatment with 0.1% DMSO vehicle or 10 nM 17b-estradiol for 4 hr.
Research resource: global identification of estrogen receptor β target genes in triple negative breast cancer cells.
No sample metadata fields
View SamplesWe examined transcriptome-wide effects of pertrurbation in KLF10 function (siKLF10) on TGFß-regulated genes and EMT in two different cells lines: A549 and Panc1. Overall design: We performed mRNA sequencing from A549 and Panc1 cells following following TGFß treatment and KLF10 knockdown. The mRNA-Seq includes following conditions: siControl, siKLF10, TGFß, siKLF10+TGFß (A549 and Panc1 cells). mRNA-sequencing was performed in duplicates for A549 and triplicates for Panc1 cells.
Krüppel-like Transcription Factor KLF10 Suppresses TGFβ-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism.
Cell line, Subject
View SamplesPurpose: ATG41 is involved both in autophagy and zinc-deficient growth. The goal of this study is to compare transcriptomic profiles of wild-type and atg41? strains to discover autophagy-independent molecular phenotypes for the mutant. The atg1? mutant is a control for autophagy activity. Methods: Wild-type and mutant yeast were grown to mid-log phase in replete medium and shifted to zinc-deficient medium for 8 hours, after which, cells were harvested for RNA sequencing to detect differential gene expression. Results: Gene expression data for virtually every gene (~6,000) was obtained with ~12,000,000 reads per sample. Differential gene expression analysis showed that several hundred genes were differentially experessed in the atg41? mutant (greater than 2-fold) at an FDR of 0.5. Conclusions: Most strikingly, we found that the atg41? mutant transcriptome shows signs that sulfur metabolism is distrupted during zinc-deficinet growth. Expression of Met4 gene targets is increased. Overall design: mRNA from wild-type, atg1?, and atg41? yeast strains was prepared from zinc-deficient cultures in quadruplicate and sequenced. Single-end, 100bp sequencing was performed, using v4 SBS chemistry on an Illumina HiSeq2500 sequencer.
An Autophagy-Independent Role for <i>ATG41</i> in Sulfur Metabolism During Zinc Deficiency.
Cell line, Subject
View SamplesHerein we describe a molecular portrait of potentially curable, Gleason 7 and intermediate risk prostate cancer based on genome-wide CNV profiles of 96 patients, and subsequent whole-genome sequencing of 28 tumours from 10 patients, using DNA quantities that are achievable in diagnostic biopsies (50 ng). We show that Gleason 7 cancer is highly heterogeneous at the SNV, CNV, and intra-chromosomal translocation levels, and is characterized by a very low number of recurrent SNVs but significant structural variation. We identified a novel recurrent MYCL1 amplification, which was strongly associated with TP53 deletion and prognostic for biochemical recurrence in this cohort. Moreover, we identified clear evidence of divergent tumour evolution in multi focal cancer and, in 2/5 cases evaluated, multiple tumours of independent clonal origin. Taken together, these data represent the first systematic evaluation of the differential genomics of potentially curable prostate cancer, and strongly suggest that a more robust understanding of the relationship between genetic heterogeneity and clinical outcomes is required to effectively develop biomarkers of prognosis based on tumour genomics.
Spatial genomic heterogeneity within localized, multifocal prostate cancer.
Specimen part, Cell line
View SamplesWe examined context specific function of BRD4 in promoting lineage specific gene expression and show that BRD4 is essential for osteoblast differentiation. Overall design: We performed mRNA sequencing from hFOB cells (undifferentiated and differentiated for 5 days into osteoblastic lineage) following BRD4 inhibition by JQ1 or siRNA mediated depletion. The mRNA-Seq includes namely 7 conditions: undifferentiated hFOBs treated with DMSO or non-targeting control siRNA (siCNTR), differentiated hFOBs with DMSO or siCNTR treatments; differentiated hFOBs treated with JQ1 or two siRNAs against BRD4 (#3 & #4). The libraries were performed in triplicates.
BRD4 localization to lineage-specific enhancers is associated with a distinct transcription factor repertoire.
Specimen part, Treatment, Subject
View Samples