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GSE43053
Rattus norvegicus
6 Downloadable Samples
Affymetrix Rat Gene 1.0 ST Array (ragene10st)
Description
Objective: identify novel and relevant aspects of Sorafenib action on liver cancer cells. We found that in rat hepatocholangiocarcinoma (LCSC-2) cells, exposure to the MEK/multikinase inhibitor sorafenib did not inhibit ERK phosphorylation nor induced appreciable cell death in the low micromolar range; instead, the drug elicited a raise of intracellular reactive oxygen species (ROS) accompanied by a severe decrease of oxygen consumption and intracellular ATP levels, all changes consistent with mitochondrial damage. Moreover, Sorafenib induced depolarization of isolated rat liver mitochondria, indicating a possible direct effect on the organelle. Microarray analysis of gene expression in sorafenib-trated cells revealed a metabolic reprogramming toward aerobic glycolysis, that likely accounts for resitance to drug toxicity in this cell line. Importantly, cytotoxicity was strongly potentiated by glucose withdrawal from the culture medium or by the glycolytic inhibitor 2-deoxy-glucose, a finding also confirmed in the highly malignant melanoma cell line B16F10. Mechanistic studies revealed that ROS are pivotal to cell killing by the Sorafenib + 2DG combination, and that a low content of intracellular oxidants is associated with resistance to the drug; instead, Thr172phosphorylation/activation of the AMP-activated protein kinase (AMPK), induced by Sorafenib, may exert protective effects, since cytotoxicity was enhanced by an AMPK specific inhibitor and prevented by the AMPK activator Metformin. Overall, this study identifies novel and relevant aspects of Sorafenib action on liver cancer cells, including mitochondrial damage, induction of ROS and a metabolic cell reprogramming towards glucose addiction, potentially exploitable in therapy.
Publication Title
The multikinase inhibitor Sorafenib enhances glycolysis and synergizes with glycolysis blockade for cancer cell killing.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 66 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Gene expression profile studies have identified an interferon signature in whole blood or mononuclear cell samples from patients with systemic lupus erythematosus. This study was designed to determine whether specific lymphocyte and myeloid subsets freshly isolated from the blood of systemic lupus erythematosus patients demonstrated unique gene expression profiles compared to subsets isolated from healthy controls.
Publication Title
Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
Illumina HiSeq 4000
Description
Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorders (ASD) identified to date. Here, we report that Chd8 heterozygous mice display increased brain size, motor delay, hypertelorism, pronounced hypoactivity, and anomalous responses to social stimuli. Whereas gene expression in the neocortex is only mildly affected at mid gestation, over 600 genes are differentially expressed in the early postnatal neocortex. Genes involved in cell adhesion and axon guidance are particularly prominent amongst the downregulated transcripts. Resting-state functional MRI identified increased synchronized activity in corticohippocampal and auditory-parietal networks in Chd8 heterozygous mutant mice, implicating altered connectivity as a potential mechanism underlying the behavioral phenotypes. Together, these data suggest that altered brain growth and diminished expression of important neurodevelopmental genes that regulate long-range brain wiring are followed by distinctive anomalies in functional brain connectivity in Chd8 +/- mice. Human imaging studies have reported altered functional connectivity in ASD patients, with long-range under-connectivity seemingly more frequent. Our data suggest that CHD8 haploinsufficiency represents a specific subtype of ASD where neuropsychiatric symptoms are underpinned by long-range over-connectivity. Overall design: RNA was isolated from microdissected cortices at E12.5 (both hemispheres) and P5 (one hemisphere and DNase-treated using the Direct-zol RNA MiniPrep kit (Zymo Research) according to the manufacturer?s instructions (n = 3 per experimental group). cDNA was end-repaired, adaptor-ligated, and A-tailed. Samples were sequenced over 2 lanes of the Illumina HiSEq 4000 platform.
Publication Title
Altered Neocortical Gene Expression, Brain Overgrowth and Functional Over-Connectivity in Chd8 Haploinsufficient Mice.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
- Illumina human-6 v2.0 expression beadchip
Description
PRC, a member of the PGC-1 coactivator family, is responsive to serum growth factors and up regulated in proliferating cells. Here, we investigated its in vivo role by stably silencing PRC expression with two different short hairpin RNAs (shRNA#1 and shRNA#4) that were lentivirally introduced into U2OS cells. ShRNA#1 transductants exhibited nearly complete knockdown of PRC protein whereas shRNA#4 transductants expressed PRC protein at approximately 15 percent of the control level. Complete PRC silencing by shRNA#1 resulted in a severe inhibition of respiratory growth, reduced expression of respiratory protein subunits from complexes I, II, III and IV, markedly lower complex I and IV respiratory enzyme levels and diminished mitochondrial ATP production. Surprisingly, shRNA#1 transductants exhibited a striking proliferation of abnormal mitochondria that were devoid of organized cristae and displayed severe membrane abnormalities. Although shRNA#4 transductants had normal respiratory subunit expression and a moderately diminished respiratory growth rate, both transductants showed markedly reduced growth on glucose accompanied by inhibition of G1/S cell cycle progression. Microarray analysis revealed striking overlaps in the genes affected by PRC silencing in the two transductants and the functional identities of these overlapping genes were consistent with the observed mitochondrial and cell growth phenotypes. The consistency between phenotype and PRC expression levels in the two independent transductant lines argues that the defects result from PRC silencing and not from off target effects. These results support a role for PRC in the integration of pathways directing mitochondrial respiratory function and cell growth.
Publication Title
Short hairpin RNA-mediated silencing of PRC (PGC-1-related coactivator) results in a severe respiratory chain deficiency associated with the proliferation of aberrant mitochondria.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 16 Downloadable Samples
- Illumina Genome Analyzer IIx
Description
We report that TAF3, a TBP-associated core promoter factor, is highly enriched in ES cells. In addition to its role in the core promoter recognition complex TFIID, genome-wide binding studies reveal that TAF3 localizes to chromosomal regions bound by CTCF and cohesin. Enrichment for TAF3/CTCF/cohesin bound regions distinguishes TAF3-activated from TAF3-repressed genes. Our findings support a new role of TAF3 in mediating long-range chromatin regulatory interactions to safeguard the finely-balanced transcriptional programs that give rise to pluripotency. Overall design: Comparison of genome-wide expression patterns between TAF3-knockdown and WT embryonic stem cells using mRNA-Seq. Significantly differentially expressed protein-coding genes were identified by comparing control and knock-down samples at each timepoint (ES, embryoid body day 3 (EB3), EB6). Single and paired-end samples were combined at each timepoint, resulting in 3 tests for each gene (based on 8, 4, 4 independent measurements at ES ,EB3, EB6, respectively).
Publication Title
Control of embryonic stem cell lineage commitment by core promoter factor, TAF3.
Sample Metadata Fields
Specimen part, Cell line, Subject, Time
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Phosphatidylcholine transfer protein (PC-TP, a.k.a StarD2) is abundantly expressed in liver and is regulated by PPAR. When fed the synthetic PPAR ligand fenofibrate, Pctp-/- mice exhibited altered lipid and glucose homeostasis. Microarray profiling of liver from fenofibrate fed wild type and Pctp-/- mice revealed differential expression of a broad array of metabolic genes, as well as their regulatory transcription factors. Because its expression controlled the transcriptional activities of both PPAR and HNF4 in cell culture, the broader impact of PC-TP on nutrient metabolism is most likely secondary to its role in fatty acid metabolism.
Publication Title
Regulatory role for phosphatidylcholine transfer protein/StarD2 in the metabolic response to peroxisome proliferator activated receptor alpha (PPARalpha).
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Saccharomyces cerevisiae
- 6 Downloadable Samples
- Affymetrix Yeast Genome 2.0 Array (yeast2)
Description
Characterize the gpm1 mutant growth on dual substrate of ethanol and glycerol
Publication Title
Phosphoglycerate mutase knock-out mutant Saccharomyces cerevisiae: physiological investigation and transcriptome analysis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 2 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Pirin (PIR) is a putative transcriptional regulator whose expression is silenced in cells bearing the AML1/ETO and PML/RAR leukemogenic fusion proteins and is significantly repressed in a large proportion of acute myeloid leukemias. PIR expression increases during in vitro myeloid differentiation of primary hematopoietic precursor cells, and ablation of PIR in the U937 myelomonocytic cell line or in murine primary hematopoietic precursor cells results in impairment of terminal myeloid differentiation.
Publication Title
Pirin downregulation is a feature of AML and leads to impairment of terminal myeloid differentiation.
Sample Metadata Fields
Cell line
View Samples- Rattus norvegicus
- 48 Downloadable Samples
- Affymetrix Rat Gene 1.0 ST Array (ragene10st)
Description
Ancestral environmental exposures that promote epigenetic transgenerational inheritance influence all aspects of an individuals life history. Stress experienced during adolescence can affect adult physiological and behavioural phenotypes. The current study utilized a systems biology approach to investigate the interactions of these two forms of epigenetic modification, one carried in the germline transgenerationally and the other contained in the context of life history. A transgenerational epigenetic imprint left by the fungicide vinclozolin promoted regional specific brain gene networks that influenced chronic restraint stress responses to alter adult physiological, brain and behavioural phenotypes. The environmentally-induced epigenetic transgenerational inheritance was found to interact with early life stress response to impact the adult brain genome activity to bring the phenotype into being.
Publication Title
Epigenetic transgenerational inheritance of altered stress responses.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 28 Downloadable Samples
- Affymetrix Human Genome U95A Array (hgu95a)
Description
Disuse atrophy is a common clinical phenomenon which significantly impacts muscle function and activities of daily living. In this study, we did expression profiling to identify transcriptional pathways associated with muscle remodeling in a clinical model of disuse.
Publication Title
Transcriptional pathways associated with skeletal muscle disuse atrophy in humans.
Sample Metadata Fields
Disease, Disease stage
View Samples