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Mus musculus
20 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Reversible protein acetylation provides a central mechanism for controlling gene expression and cellular signaling events. It is governed by the antagonistic commitment of two enzymes families: the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). HDAC4, like its class IIa counterparts, is a potent transcriptional repressor through interactions with tissue-specific transcription factors via its N-terminal domain. Whilst the lysine deacetylase activity of the class IIa HDACs is much less potent than that of the class I enzymes, HDAC4 has been reported to influence protein deacetylation through its interaction with HDAC3.
Publication Title
HDAC4 does not act as a protein deacetylase in the postnatal murine brain in vivo.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 48 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
To dissect the impact of nuclear and extranuclear mutant htt on the initiation and progression of disease, we generated a series of transgenic mouse lines in which nuclear localization (NLS) or nuclear export sequences (NES) have been placed N-terminal to the htt exon 1 protein carrying 144 glutamines. Our data indicate that the exon 1 mutant protein is present in the nucleus as part of an oligomeric or aggregation complex. Increasing the concentration of the mutant transprotein in the nucleus is sufficient for, and dramatically accelerates the onset and progression of behavioral phenotypes. Furthermore, nuclear exon 1 mutant protein is sufficient to induce cytoplasmic neurodegeneration and transcriptional dysregulation. However, our data suggests that cytoplasmic mutant exon 1 htt, if present, contributes to disease progression.
Publication Title
Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 71 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 37 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntingtons disease (HD), a protein folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion and transcriptional dysregulation. We found that HDAC4 interacts with huntingtin in a polyglutamine-length dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor co-ordination, neurological phenotypes and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for cytoplasmic aggregation in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation which may be amenable to small molecule therapeutics.
Publication Title
HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 34 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntingtons disease (HD), a protein folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion and transcriptional dysregulation. We found that HDAC4 interacts with huntingtin in a polyglutamine-length dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor co-ordination, neurological phenotypes and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for cytoplasmic aggregation in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation which may be amenable to small molecule therapeutics.
Publication Title
HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Rattus norvegicus
- 44 Downloadable Samples
- Affymetrix Rat Genome U34 Array (rgu34a)
Description
We used microarrays to analyze gene expression changes in liver after treatment of rats with two compounds from drug development (R1, R2) to identify potential effects related to hepatotoxicity.
Publication Title
Gene expression-based in vivo and in vitro prediction of liver toxicity allows compound selection at an early stage of drug development.
Sample Metadata Fields
Sex, Specimen part, Treatment
View Samples- Mus musculus, Homo sapiens
- 66 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a), Affymetrix Human Genome U133A Array (hgu133a)
Description
Acute lung rejection is a risk factor for chronic rejection, jeopardizing the long-term survival of lung transplant recipients. At present, acute rejection is diagnosed by transbronchial lung biopsies, which are invasive, expensive, and subject to significant sampling error. In this study, we sought to identify groups of genes whose collective expression in BAL cells best classifies acute rejection versus no-rejection. BAL samples were analyzed from 32 unique subjects whose concurrent histology showed acute rejection (n=14) or no rejection (n=18). Global BAL cell gene expression was measured using Affymetrix U133A microarrays. The nearest shrunken centroid method with 10-fold cross validation was used to define the classification model. 250 runs of the algorithm were performed to determine the range of misclassification error and the most influential genes in determining classifiers. The estimated overall misclassification rate was below 20%. Seven transcripts were present in every classifier and 52 transcripts were present in at least 70% of classifiers; these transcripts were notable for involvement with T-cell function, cytotoxic CD8 activity, and granulocyte degranulation. The proportions of both lymphocytes and neutrophils in BAL samples increased with increasing probability of acute rejection; this trend was more pronounced with neutrophils. We conclude that there is a prominent acute rejection-associated signature in BAL cells characterized by increased T-cell, CD8+ cytotoxic cell, and neutrophil gene expression; this is consistent with established mechanistic concepts of the acute rejection response.
Publication Title
Bronchoalveolar lavage cell gene expression in acute lung rejection: development of a diagnostic classifier.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 37 Downloadable Samples
Illumina Genome Analyzer II, Illumina HiSeq 2000
Description
The ability to sequence genomes has far outstripped approaches for deciphering the information they encode. Here we present a suite of techniques, based on ribosome profiling (the deep-sequencing of ribosome-protected mRNA fragments), to provide genome-wide maps of protein synthesis as well as a pulse-chase strategy for determining rates of translation elongation. We exploit the propensity of harringtonine to cause ribosomes to accumulate at sites of translation initiation together with a machine learning algorithm to define protein products systematically. Analysis of translation in mouse embryonic stem cells reveals thousands of strong pause sites and novel translation products. These include amino-terminal extensions and truncations and upstream open reading frames with regulatory potential, initiated at both AUG and non-AUG codons, whose translation changes after differentiation. We also define a new class of short, polycistronic ribosome-associated coding RNAs (sprcRNAs) that encode small proteins. Our studies reveal an unanticipated complexity to mammalian proteomes. Overall design: Examination of translation in mouse embryonic stem cells and during differentiation into embryoid bodies
Publication Title
Ribosome profiling provides evidence that large noncoding RNAs do not encode proteins.
Sample Metadata Fields
Cell line, Treatment, Subject
View Samples
GSE2018- Homo sapiens
- 34 Downloadable Samples
Affymetrix Human Genome U133A Array (hgu133a)
Description
Bronchoalveolar lavage samples collected from lung transplant recipients. Numeric portion of sample name is an arbitrary patient ID and AxBx number indicates the perivascular (A) and bronchiolar (B) scores from biopsies collected on the same day as the BAL fluid was collected. Several patients have more than one sample in this series and can be determined by patient number followed by a lower case letter. Acute rejection state is determined by the combined A and B score - specifically, a combined AB score of 2 or greater is considered an acute rejection.
Publication Title
Gene expression profiling of bronchoalveolar lavage cells in acute lung rejection.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
- IlluminaHiSeq2000
Description
Influenza A viruses generate annual epidemics and occasional pandemics of respiratory disease with important consequences for human health and economy. Therefore, a large effort has been devoted to the development of new anti-influenza drugs directed to viral targets, as well as to the identification of cellular targets amenable for anti-influenza therapy. Here we describe a new approach to identify such potential cellular targets by screening collections of drugs approved for human use. We reasoned that this would most probably ensure addressing a cellular target and, if successful, the compound would have a well known pharmacological profile. In addition, we reasoned that a screening using a GFP-based recombinant replicon system would address virus trancription/replication and/or gene expression, and hence address a stage in virus infection more useful for inhibition. By using such strategy we identified Montelukast as an inhibitor of virus gene expression, which reduced virus multiplication in virus-infected cells but did not alter virus RNA synthesis in vitro or viral RNA accumulation in vivo. By deep sequencing of RNA isolated from mock- and virus-infected human cells, treated or not with Montelukast, we identified the PERK-mediated unfolded protein response as the pathway responsible for Montelukast action. Accordingly, PERK phosphorylation was inhibited in infected cells but stimulated in Montelukast-treated cells. These results suggest the PERK-mediated unfolded protein response as a potential cellular target to modulate influenza virus infection. Overall design: Comparison of gene expression measured by deep sequencing (single-ends, 50nt, RNA-seq) of "Infected", "Not infected", "Infected+Montelukast" and "Not infect+Montelukast" in human A549 cells. Infected means "Infected with influenza virus".
Publication Title
Chemical Genomics Identifies the PERK-Mediated Unfolded Protein Stress Response as a Cellular Target for Influenza Virus Inhibition.
Sample Metadata Fields
No sample metadata fields
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