Early transcriptional changes linked to naturally occurring Huntington's disease mutations in human embryonic stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE34201 | GEO | 2012/06/20
SECONDARY ACCESSION(S): PRJNA149841
REPOSITORIES: GEO
Similar Datasets
Project description:Multiple human embryonic stem (ES) cell lines derived from blastocysts diagnosed as carrying the mutant huntingtin gene by pre-implantation diagnosis were used to explore early developmental changes in gene expression. How mutant huntingtin impacts on signalling pathways in the pre-symptomatic period has remained essentially unexplored in humans due to a previous lack of appropriate models. Total RNA was isolated from 10 human ES cell lines, 6 HD and 4 wild type control, and their neural stem cell (NSC) progeny.
2012-06-19 | E-GEOD-34201 | biostudies-arrayexpress
Project description:Expressing a mutant fragment of huntingtin (Htt) in yeast produces several HD-relevant phenotypes. We used microarrays to study global change in expression induced by this mutant htt fragment. Expression was also analysed in three suppressor deletion strains expressing a toxic mutant htt fragment: bna4Δ, mbf1Δ, and ume1Δ.
2010-11-09 | GSE18644 | GEO
Project description:Selective neuronal vulnerability is a common, yet poorly understood characteristic of neurodegenerative diseases and is particularly prominent in Huntington's disease (HD). To determine how presence of mutant prion protein influences gene expression at pre-symptomatic stages, we used RiboTag to isolate cell type-specific, translating RNA from GABAergic, glutamatergic, somatostatin- (SST) and parvalbumin-expressing neurons of 9-month-old knock-in mice of heterozygous for a Q185 expansion in the endogenous Hdh gene or littermate controls.
2022-11-04 | GSE199837 | GEO
Project description:Huntington’s 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.
2011-08-23 | GSE9038 | GEO
Project description:Transcriptional dysregulation has emerged as a core pathologic feature of Huntington's disease (HD), one of several triplet-repeat disorders characterized by movement deficits and cognitive dysfunction. Although the mechanisms contributing to the gene expression deficits remain unknown, therapeutic strategies have aimed to improve transcriptional output via modulation of chromatin structure. Recent studies have demonstrated therapeutic effects of commercially available histone deacetylase (HDAC) inhibitors in several HD models; however, the therapeutic value of these compounds is limited by their toxic effects. Here, beneficial effects of a novel pimelic diphenylamide HDAC inhibitor, HDACi 4b, in an HD mouse model are reported. Chronic oral administration of HDACi 4b, beginning after the onset of motor deficits, significantly improved motor performance, overall appearance, and body weight of symptomatic R6/2(300Q) transgenic mice. These effects were associated with significant attenuation of gross brain-size decline and striatal atrophy. Microarray studies revealed that HDACi 4b treatment ameliorated, in part, alterations in gene expression caused by the presence of mutant huntingtin protein in the striatum, cortex, and cerebellum of R6/2(300Q) transgenic mice. For selected genes, HDACi 4b treatment reversed histone H3 hypoacetylation observed in the presence of mutant huntingtin, in association with correction of mRNA expression levels. These findings suggest that HDACi 4b, and possibly related HDAC inhibitors, may offer clinical benefit for HD patients and provide a novel set of potential biomarkers for clinical assessment.
2010-12-27 | GSE26317 | GEO
Project description:Transcriptional dysregulation has emerged as a core pathologic feature of Huntington's disease (HD), one of several triplet-repeat disorders characterized by movement deficits and cognitive dysfunction. Although the mechanisms contributing to the gene expression deficits remain unknown, therapeutic strategies have aimed to improve transcriptional output via modulation of chromatin structure. Recent studies have demonstrated therapeutic effects of commercially available histone deacetylase (HDAC) inhibitors in several HD models; however, the therapeutic value of these compounds is limited by their toxic effects. Here, beneficial effects of a novel pimelic diphenylamide HDAC inhibitor, HDACi 4b, in an HD mouse model are reported. Chronic oral administration of HDACi 4b, beginning after the onset of motor deficits, significantly improved motor performance, overall appearance, and body weight of symptomatic R6/2(300Q) transgenic mice. These effects were associated with significant attenuation of gross brain-size decline and striatal atrophy. Microarray studies revealed that HDACi 4b treatment ameliorated, in part, alterations in gene expression caused by the presence of mutant huntingtin protein in the striatum, cortex, and cerebellum of R6/2(300Q) transgenic mice. For selected genes, HDACi 4b treatment reversed histone H3 hypoacetylation observed in the presence of mutant huntingtin, in association with correction of mRNA expression levels. These findings suggest that HDACi 4b, and possibly related HDAC inhibitors, may offer clinical benefit for HD patients and provide a novel set of potential biomarkers for clinical assessment. Analysis of striatum, cortex, and cerebellum from R6/2(300Q) transgenic mice before and after treatment with the HDAC inhibitor 4b
2010-12-27 | E-GEOD-26317 | biostudies-arrayexpress
Project description:Analysis of proteomic consequences of Tyrobp deletion in a Huntington's disease mouse model. Examination of protein expression alterations in the striatum of mutant huntingtin-Q175 with and without TYROBP (protein tyrosine kinase-binding protein).
2022-01-05 | MSV000088643 | MassIVE
Project description:The molecular nature of malignant tumors is well studied in vertebrates, while their evolutionary origin remains unknown. In particular, there is no evidence for naturally occurring malignant tumors in pre-bilaterian animals, such as sponges and cnidarians. This is somewhat surprising given that recent computational studies have predicted that all metazoans are prone to develop tumors. Here we provide first evidence for naturally occurring tumors in Hydra oligactis. Histological, cellular and molecular data reveal that these tumors are transplantable and caused by differentiation arrest of female gametes. Growth of tumor cells is independent from the cellular environment. Tumor bearing polyps have significantly reduced fitness. In addition, Hydra tumors show a greatly altered transcriptome that mimics expression shifts in vertebrate cancers. Therefore, this study shows, that invasive tumors have deep roots in animal phylogeny, and that early branching animals may be informative in revealing the fundamental mechanisms of tumorigenesis.
2014-06-24 | GSE56287 | GEO
Project description:Huntington’s 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. Total RNA was isolated from striatum and cerebellum of Hdh CAG knock-in mice (HdhQ111/HdhQ111) and wild-type mice (Hdh+/Hdh+, 3~10 weeks) for gene expression profiling using Affymetrix MG430 2.0 arrays.
2011-08-22 | E-GEOD-9038 | biostudies-arrayexpress
Project description:We have investigated the process of disease-induced functional perturbation and the related transcriptional changes occurring in thoraco-lumbar spinal cord extracted from Sprague-Dawley rats heterozygous for the G93A SOD1 gene mutation (Emerging Model 2148 Het Male, Taconic USA; Wyeth and Amyotrophic Lateral Sclerosis Association 2002) using spinal cord from wild type females littermates as reference tissues. Rats were obtained from a breeding project at Taconic Breeding Services (USA). We have applied large-scale gene expression analysis to define the pattern or transcriptional changes occurring in spinal cord from the G93A SOD1 rat model from a pre-symptomatic stage, at disease onset and at end-stage disease, using Bead Array analysis (Illumina, San Diego, USA). We have pooled spinal cord from N:5 transgenic rats for each of the time points considered, using the same pools of spinal cord from sex and age-matched WT rats as reference. In this specific project, the aim was to obtain a gene ontology (GO) pathway analysis of the transcriptional changes induced by the G93A SOD1 mutation in rat spinal cord. Hence, we have opted for a sample pooling strategy, well aware that in so doing, we would not obtaineed information about individuals genes variation across the samples in study but an overall view of the activation of multi-genes molecular signals. Total RNA was isolated from the spinal cords of mutant (G93A SOD1 gene mutation) female rats sacrificed at a pre-symptomatic stage (10-week old), at disease onset and at end stage disease and from age and sex-matched wild type (WT) littermates. RNA samples obtained from spinal cord extracted from rats of the same genetic types and sacrificed at the same time points (e.g. 5 RNA samples from mutant spinal cord from end-stage rats; 5 RNA samples from mutant spinal cord from rats at disease onset; 5 RNA samples from mutant pre-symptomatic rats and 5 RNA samples from spinal cord obtained from age-matched WT rats sacrificed at each of the 3 time points) were pooled and used for gene expression analysis and Ontology analysis of the expression profiles.
2010-06-23 | E-GEOD-20894 | biostudies-arrayexpress