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SRP094956
Mus musculus
4 Downloadable Samples
Illumina Genome Analyzer IIx
Description
Synaptic activity drives changes in gene expression to promote long-lasting adaptations of neuronal structure and function. One example of such an adaptive response is the buildup of acquired neuroprotection, a synaptic activity- and gene transcription-mediated increase in the resistance of neurons against harmful conditions. A hallmark of acquired neuroprotection is the stabilization of mitochondrial structure and function. We therefore re-examined previously identified sets of synaptic activity-regulated genes to identify genes that are directly linked to mitochondrial function. In mouse and rat primary hippocampal cultures synaptic activity caused an upregulation of glycolytic genes and a concomitant downregulation of genes required for oxidative phosphorylation, mitochondrial biogenesis and maintenance. Changes in metabolic gene expression were induced by action potential bursting, but not by glutamate bath application activating extrasynaptic NMDA receptors. The specific pattern of gene expression changes suggested that synaptic activity promotes a shift of neuronal energy metabolism from oxidative phosphorylation toward aerobic glycolysis, also known as Warburg effect. The ability of neurons to upregulate glycolysis has, however, been debated. We therefore used FACS sorting to show that, in mixed neuron glia co-cultures, activity-dependent regulation of metabolic gene expression occurred in neurons. Changes in gene expression were accompanied by changes in the phosphorylation-dependent regulation of the key metabolic enzyme, pyruvate dehydrogenase. Finally, increased synaptic activity caused an increase in the ratio of L-lactate production to oxygen consumption in primary hippocampal cultures. Based on these data we suggest the existence of a synaptic activity-mediated neuronal Warburg effect that may promote mitochondrial homeostasis and neuroprotection. Overall design: We compared the mRNA expression profile of primary hippocampal neurons after 4h of basal synaptic activity vs. 4h of action potential bursting. Two independent experiments with independent cell preparations were performed.
Publication Title
Synaptic Activity Drives a Genomic Program That Promotes a Neuronal Warburg Effect.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 9 Downloadable Samples
- Illumina HiSeq 2000
Description
The formation of long-term memory requires signaling from the synapse to the nucleus to mediate neuronal activity-dependent gene transcription. Synapse-to-nucleus communication is initiated by influx of calcium ions through synaptic NMDA receptors and/or L-type voltage-gated calcium channels and involves the activation of transcription factors by calcium/calmodulin signaling in the nucleus. Recent studies have drawn attention to a new family of transcriptional regulators, the so-called calmodulin-binding transcription activator (CAMTA) proteins. CAMTAs are expressed at particularly high levels in the mouse and human brain, and we reasoned that, as calmodulin-binding transcription factors, CAMTAs may regulate the formation of long-term memory by coupling synaptic activity and calcium/calmodulin signaling to memory-related transcriptional responses. This hypothesis is supported by genetic studies that reported a correlation between CAMTA gene polymorphisms or mutations and cognitive capability in humans. Here, we show that acute knock-down of CAMTA1, but not CAMTA2, in the hippocampus of adult mice results in impaired performance in two memory tests, contextual fear conditioning and object-place recognition test. Short-term memory and neuronal morphology were not affected by CAMTA knock-down. Gene expression profiling in the hippocampus of control and CAMTA knock-down mice revealed a number of putative CAMTA1 target genes related to synaptic transmission and neuronal excitability. Patch clamp recordings in organotypic hippocampal slice cultures provided further evidence for CAMTA1-dependent changes in electrophysiological properties. In summary, our study provides experimental evidence that confirms previous human genetic studies and establishes CAMTA1 as a regulator of long-term memory formation. Overall design: We compared the mRNA expression profile of three groups, i.e. mice infected with a recombinant adeno-associated virus (rAAV) expressing a non-targeting control shRNA, mice infected with a rAAV expressing Camta1 targeting shRNA sequence A, and mice infected with a rAAV expressing Camta1 targeting shRNA sequence B. Three animals were used per group.
Publication Title
The calmodulin-binding transcription activator CAMTA1 is required for long-term memory formation in mice.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Sox2 is required to maintain osteosarcoma cell tumor initiation.Knockdown of Sox2 leads tpo loss of tumorigenic properties. To examine gene expression changes upon Sox2 knockdown, we performed microarray analysis on mouse osteosarcoma cells expressing scrambled or Sox2shRNA. We found that genes upregulated upon Sox2 knockdown included osteoblast diffrentiation genes and genes down regulated included cell cycle and RNA processing genes as well as YAP-TEAD target genes.
Publication Title
Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2000
Description
The Mediator complex regulates gene transcription by linking basal transcriptional machinery with DNA-bound transcription factors. The activity of the Mediator complex is mainly controlled by a kinase submodule that is comprised of four proteins, including MED12. Although ubiquitously expressed, Mediator subunits can differentially regulate gene expression in a tissue-specific manner. Here, we report that MED12 is required for normal cardiac function such that mice with conditional cardiac-specific deletion of MED12 display progressive dilated cardiomyopathy. Loss of MED12 perturbs expression of calcium handling genes in the heart, consequently altering calcium cycling in cardiomyocytes and disrupting cardiac electrical activity. We identified transcription factors that regulate expression of calcium-handling genes that are downregulated in the heart in the absence of MED12, and found that MED12 localizes to transcription factor consensus sequences within calcium handling genes. We showed that MED12 interacts with one such transcription factor, MEF2, in cardiomyocytes, and that MED12 and MEF2 co-occupy promoters of calcium handling genes. Furthermore, we demonstrated that MED12 enhances MEF2 transcriptional activity and overexpression of both increases expression of calcium handling genes in cardiomyocytes. Our data support a role for MED12 as a coordinator of transcription through MEF2 and other transcription factors. We conclude that MED12 is a regulator of a network of calcium handling genes, consequently “mediating” contractility in the mammalian heart. Overall design: Ventricle mRNA profiles of 1-day old control (CTL, CreNEG) and cardiac-specific Med12 knockout mice (Med12cKO, CrePOS) were generated by deep sequencing, in triplicate, using Illumina.
Publication Title
MED12 regulates a transcriptional network of calcium-handling genes in the heart.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 33 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Anaplastic large-cell lymphoma (ALCL) makes up approximately 15% of paediatric non-Hodgkin's lymphomas of childhood. The vast majority of them is associated with the t(2;5)(p23;q35) translocation that results in the expression of a hybrid oncogenic tyrosine kinase, NPM-ALK. In order to investigate ALCL biological characteristics we used transcriptional profiling approach. Genome-wide gene expression profiling, performed on 23 paediatric ALCL and 12 reactive lymph nodes specimens, showed two novel ALCL subgroups based on their NPM-ALK expression levels (named (ALK low and ALK high). Gene set enrichment analysis revealed, in ALK low samples, a positive enrichment of genes involved in the Interleukin signaling pathway, whereas we found increased expression of genes related to cell cycle progression and division in ALK high tumour samples, such as Aurora Kinase A (AURKA) and B (AURKB). Growth inhibition was observed upon administration of AURKA and AURKB inhibitors Alisertib and Barasertib and it was associated with perturbation of the cell cycle and induction of apoptosis. In conclusion we identified two novel ALCL subgroups, which display unique biological characteristics suggesting sensitivity to distinct targeted therapies.
Publication Title
NPM-ALK expression levels identify two distinct subtypes of paediatric anaplastic large cell lymphoma.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 81 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Acute lymphoblastic pediatric leukemia specimens without known genetic hallmarks are examined for hidden genomic aberrancies and related gene expression profiles
Publication Title
Integration of genomic and gene expression data of childhood ALL without known aberrations identifies subgroups with specific genetic hallmarks.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 2500
Description
The heart requires a continuous supply of energy but has little capacity for energy storage and thus relies on exogenous metabolic sources. We previously showed that cardiac MED13 modulates systemic energy homeostasis in mice. Here we sought to define the extra-cardiac tissue(s) that respond to cardiac MED13 signaling. We show that cardiac over-expression of MED13 in transgenic (MED13cTg) mice confers a lean phenotype that is associated with increased lipid uptake, beta-oxidation and mitochondrial content in white adipose tissue (WAT) and liver. Cardiac expression of MED13 decreases metabolic gene expression and metabolite levels in heart and liver but enhances them in WAT. Although exhibiting increased energy expenditure in the fed state, MED13cTg mice metabolically adapt to fasting. Furthermore, MED13cTg hearts oxidize fuel that is readily available, rendering them more efficient in the fed state. Parabiosis experiments in which circulations of wild-type and MED13cTg mice are joined, reveal that circulating factor(s) in MED13cTg mice promote enhanced metabolism and leanness. These findings demonstrate that MED13 acts within the heart to promote systemic energy expenditure in extra-cardiac energy depots and point to an unexplored metabolic communication system between the heart and other tissues. Overall design: n=3 for each genotype and organ
Publication Title
MED13-dependent signaling from the heart confers leanness by enhancing metabolism in adipose tissue and liver.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 80 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Patients with metastatic colorectal cancer were enrolled for treatment with cetuximab monotherapy. Transcriptional profiling was conducted on RNA from pre-treatment metastatic site biopsies to identify genes whose expression correlates with best clinical responses.
Publication Title
Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 6 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Gene expression of Double Positive, and Single Positive CD4+ human thymocytes
Publication Title
Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150.
Sample Metadata Fields
No sample metadata fields
View Samples