Filters
Technology
Platform
GSE26001
Mus musculus
24 Downloadable Samples
Description
Huntington's disease (HD) features a unique disease-initiating mechanism hypothesized to entail an impact of the CAG repeat encoded polyglutamine region on the full-length huntingtin protein, with dominant effects that are continuous with CAG size, in a simple gain of function. To evaluate these predictions, we generated a series of heterozygous Hdh CAG knock-in mouse embryonic stem (ES) cell lines, with 18, 48, 89, 109 CAGs, and found that a continuous analytic strategy efficiently identified, from genome-wide datasets, 73 genes and 172 pathways whose expression varied continuously with CAG length. The CAG-correlated genes were distinct from the set of 754 genes that distinguished huntingtin null ES cells from wild-type controls, and CAG-correlated pathways did not display a one-to-one correspondence with the 238 pathways altered in huntingtin null ES cells. Rather, the genes that varied with CAG size were either members of the same pathways as altered genes in huntingtin null cells or were members of unique pathways related to these pathways. These findings falsified a gain of function/loss of function proposal but were consistent with the simple gain of novel function mechanism hypothesis. The dominant CAG correlated gene expression changes conformed to the genetic features of the HD initiating mechanism and were system-wide and inter-related with pathways perturbed by lack of full-length huntingtin function, urging system-wide approaches for the discovery and validation of potential modulating factors, in the search for effective HD therapeutics.
Publication Title
HD CAG-correlated gene expression changes support a simple dominant gain of function.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 23 Downloadable Samples
Description
Huntingtons disease (HD) involves marked early neurodegeneration in the striatum whereas the cerebellum is relatively spared despite the ubiquitous expression of full-length mutant huntingtin, implying that inherent tissue-specific differences determine susceptibility to the HD CAG mutation. To understand this tissue specificity, we compared early mutant huntingtin-induced gene expression changes in striatum to those in cerebellum in young Hdh CAG knock-in mice, prior to onset of evident pathological alterations. Endogenous levels of full-length mutant huntingtin caused qualitatively similar, but quantitatively different gene expression changes in the two brain regions. Importantly, the quantitatively different responses in striatum and cerebellum in mutant mice were well accounted for by the intrinsic molecular differences in gene expression between striatum and cerebellum in wild-type animals. Tissue-specific gene expression changes in response to the HD mutation, therefore, appear to reflect the different inherent capacities of these tissues to buffer qualitatively similar effects of mutant huntingtin. These findings highlight a role for intrinsic quantitative tissue differences in contributing to HD pathogenesis, and likely to other neurodegenerative disorders exhibiting tissue-specificity, thereby guiding the search for effective therapeutic interventions.
Publication Title
Differential effects of the Huntington's disease CAG mutation in striatum and cerebellum are quantitative not qualitative.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
Description
We propose a method to compare the location and variability of gene ex-pression between two groups of microarrays using a permutation test based on the pairwise distance between microarrays. The microarrays could be samples from distinct clinical or biological populations or microarrays prepared at two different levels of an experimental factor. For these tests the entire microarray or some pre-specifed subset of genes, not the individual gene, is the unit of analysis. We apply this method to compare results from two dfferent protocols for preparing labeled targets for microarray hybridization and their subsequent gene expression analysis.
Publication Title
Assessing statistical significance in microarray experiments using the distance between microarrays.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
Description
MEG3 (Maternally Expressed Gene 3) is a non-coding RNA that is highly expressed in the normal human brain and pituitary. Expression of MEG3 is lost in gonadotroph-derived clinically non-functioning pituitary adenomas. Meg3 knock-out mice were generated to identify targets and potential functions of this gene in embryonic development and tumorigenesis. Gene expression profiles were compared in the brains of Meg3-null embryos and wild-type litter-mate controls using microarray analysis. Microarray data were analyzed with GeneSifter which uses Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) classifications to identify signaling cascades and functional categories of interest within the data set. Differences were found in signaling pathways and ontologies related to angiogenesis between wild-type and knock-out embryos. Quantitative RT-PCR and histological staining showed increased expression of some VEGF pathway genes and increased cortical microvessel density in the knock-out embryos. These results are consistent with reported increases in VEGF signaling observed in human clinically non-functioning pituitary adenomas. In conclusion, Meg3 may play an important role in control of vascularization in the brain and may function as a tumor suppressor by preventing angiogenesis.
Publication Title
Increased expression of angiogenic genes in the brains of mouse meg3-null embryos.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
Description
Mamamlian cardiogenesis occurs through the development of discreate populations of first and second heart field progenitors. We have used a dual transgenic color reproter system to isolate purified populations of these progenitors.
Publication Title
Generation of functional ventricular heart muscle from mouse ventricular progenitor cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
Description
In Huntingtons disease (HD), an expanded CAG repeat produces characteristic striatal neurodegeneration. Interestingly, the HD CAG repeat, whose length determines age at onset, undergoes tissue-specific somatic instability, predominant in the striatum, suggesting that tissue-specific CAG length changes could modify the disease process. Therefore, understanding the mechanisms underlying the tissue specificity of somatic instability may provide novel routes to therapies. However progress in this area has been hampered by the lack of sensitive high-throughput instability quantification methods and global approaches to identify the underlying factors.
Publication Title
A novel approach to investigate tissue-specific trinucleotide repeat instability.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 1 Downloadable Sample
Description
Gene expression in wild-type and p38a-knockout dendritic cells (DCs) were compared. Lymph node dendritic cells were isolated from mice, and left unstimulated and stimulated with Pam3CSK4, a toll-like receptor 2 agonist.
Publication Title
Cell type-specific targeting dissociates the therapeutic from the adverse effects of protein kinase inhibition in allergic skin disease.
Sample Metadata Fields
No sample metadata fields
View Samples- Danio rerio
- 1 Downloadable Sample
Description
Fluorescent-labeled zebrafish RAS-induced embryonal rhabdomyosarcoma (ERMS) were created to facilitate in vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in diverse cellular compartments. Using this strategy, we have identified a molecularly distinct ERMS cell subpopulation that expresses high levels of myf5 and is enriched for ERMS-propagating potential when compared with other tumor-derived cells. Embryonal rhabdomyosarcoma (ERMS) is an aggressive pediatric sarcoma of muscle. Here, we show that tumor-propagating potential is confined to myf5+ERMS cells and can be visualized in live, fluorescent transgenic zebrafish. During early tumor growth, myf5+ERMS cells reside within an expanded satellite cell compartment, but by late stage ERMS, myf5+cells are dynamically reorganized into distinct regions separated from differentiated tumor cells. Human ERMS also contain distinct areas of differentiated and undifferentiated cells. Time-lapse imaging revealed that myf5+ERMS cells populate newly formed tumor only after seeding by highly migratory myogenin+ ERMS cells. This finding helps explain the clinical observation that Myogenin positivity correlates with poor clinical outcome in human ERMS and suggests that differentiated tumor cells play critical roles in metastasis. One-cell stage myf5-GFP/mylz2-mCherry fluorescent transgenic zebrafish were injected with rag2-kRAS12D. A subset of animals developed ERMS. Tumor cells were transplanted into syngeneic recipient animals that lacked fluorescent reporter expression. ERMS cell subfractions were isolated from transplant animals and purified cell populations obtained following two rounds of FACS. Sorted cells were 1) analyzed by microarray/RT-PCR and 2) transplanted at limiting dilution into syngeneic animals. These experiments confirm that zebrafish ERMS contain molecularly distinct cell subfractions that express high levels of myf5-GFP and exhibit difference in gene expression when compared to other ERMS cell subtypes. All four fluorescent-labeled cell populations were analyzed (n=2 tumors total).
Publication Title
In vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in embryonal rhabdomyosarcoma.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
Description
Transcriptional dysregulation plays a major role in the pathology of Huntington's disease (HD). However, the mechanisms causing selective downregulation of genes remain unknown. Histones regulate chromatin structure and thereby control gene expression; recent studies have demonstrated a therapeutic role for histone deacetylase (HDAC) inhibitors in polyglutamine diseases. This study demonstrates that despite no change in overall acetylated histone levels, histone H3 is hypo-acetylated at promoters of downregulated genes in R6/2 mice, ST14a and STHdh cells, as demonstrated by in vivo chromatin immunoprecipitation. In addition, HDAC inhibitor treatment increases association of acetylated histones with downregulated genes and corrects mRNA abnormalities. In contrast, there is a decrease in mRNA levels in wild-type cells following treatment with a histone acetyltransferase inhibitor. Although changes in histone acetylation correlate with decreased gene expression, histone hypo-acetylation may be a late event, as no hypo-acetylation is observed in 4-week-old R6/2 mice. Nevertheless, treatment with HDAC inhibitors corrects mRNA abnormalities through modification of histone proteins and may prove to be of therapeutic value in HD.
Publication Title
No associated publication
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
Description
The aim of this study is to survey global gene expression of total thymocytes from wild-type mice and Atg16l1 mutant (hypomorph) mice.
Publication Title
No associated publication
Sample Metadata Fields
No sample metadata fields
View Samples