Gene Expression Profiling Using Huntington Disease Cell Culture Model
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE84055 | GEO | 2016/07/15
SECONDARY ACCESSION(S): PRJNA327877
REPOSITORIES: GEO
Similar Datasets
Project description:Mapping ultra-high resolution of Sp1:DNA interaction would provide us with valuable new mechanistic insights into Sp1-mediated gene regulatory network in Huntington Disease cell culture model. STHdh Q7/Q7 cells were directly fixed and used for the ChIP-exo experiment.
2016-07-15 | E-GEOD-84056 | biostudies-arrayexpress
Project description:Huntington disease (HD) is associated with increased nuclear accumulation of the repressor element-1 silencing transcription factor (REST) which govens a huge gene network. An alternative REST splicing event (∆E3) eliminates a motif essential for nuclear targeting of REST. We used Affymetrix’s GeneChip® Mouse Gene 2.0 ST Array to compare global transcription between STHdhQ111/Q111 cells (a cell model of HD) treated with specific antisense oligos (ASOs) inducing ∆E3 and a control oligo, with a comparison to normal STHdhQ7/Q7 cells.
2016-01-25 | GSE77194 | GEO
Project description:Affymetrix MG430 2.0 expression levels of wild-type (STHdhQ7/Q7), 3NP-treated wild-type (STHdhQ7/Q7+3-NP), and mutant (STHdhQ111/Q111) striatal cells Keywords: Pharmacological and genetic HD cell culture models
2007-06-20 | GSE3583 | GEO
Project description:Huntington disease is a severe neurological disorder caused by an abnormal polyglutamine expansion in the N-terminal of the huntingtin protein. Here we show that breast tumours appear earlier when mutant huntingtin is expressed in an activated polyomavirus middle T antigen (PyVT) mouse breast cancer model as compared to the control mice expressing wild-type huntingtin. Tumours bearing mutant huntingtin have a modified gene expression pattern revealing increases in the IGF-1/Akt signalling, epithelial-mesenchymal transition and metastatic properties. Indeed, polyQ-huntingtin expressing tumours show hyper-activation of Akt pathway. Also, when mutant huntingtin is expressed, cancer cells in culture change morphology and the levels of cell adhesion and mesenchymal markers are affected in primary tumour or corresponding derived cells. As a consequence, PyVT induced lung metastasis is higher in Huntington disease mice than in the control mice. Finally, analysis of cases of Huntington disease patients developing breast cancer may suggest an increased aggressiveness of breast cancer when compared to the control population. 8 Total samples were analyzed: 4 x MMTV-PyVT/HdhQ7/Q7 breast tumours; 4 x MMTV-PyVT/HdhQ111/Q111 breast tumours;
2014-04-14 | E-GEOD-28685 | biostudies-arrayexpress
Project description:Huntington Disease (HD) is a dominantly inherited, relentlessly progressive neurodegenerative disease. Caused by a polyglutamine expansion in the mutant huntingtin protein (mhtt), HD pathogenesis impairs function in the cerebral cortex and in medium spiny neurons of the striatum and involves transcriptional dysregulation of a number of genes. Of these genes, silencing of genes related to mitochondrial function is believed to explain metabolic dysfunction in rodent models of HD. Here we show that transglutaminase 2 (TG2), which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes. TG2 inhibition by RNA knockdown, genetic deletion, or administration of a novel irreversible, peptide-based TG2 inhibitor (ZDON) de-repressed two established regulators of mitochondrial function, PGC-1? and cytochrome c in a cell model of HD. TG2 must localize to non-coding or coding regions of these mitochondrial metabolic genes to silence their transcription. As expected, TG2 inhibition reversed the increased susceptibility of HD mouse cells and human HD myoblasts to the mitochondrial toxin, 3-nitroproprionic acid (3-NP); however, protection mediated by TG2 inhibition was not associated with improved mitochondrial bioenergetics. Indeed, an unbiased array analysis indicated that TG2 inhibition leads to normalization of not only mitochondrial genes but of nearly 40% of genes that are dysregulated in HD mouse striatal neurons, including chaperone and histone genes. Indeed, TG2 interacts directly with Histone 3 in the nucleus. Moreover, TG2 inhibition significantly attenuated photoreceptor degeneration in a Drosophila model of HD and protected mouse HD striatal neurons (YAC128) from NMDA- induced toxicity. Altogether these findings demonstrate that TG2 mediates its deleterious effects in HD by contributing to broad transcriptional dysregulation of genes representing many cellular functions. These studies define a novel HDAC-independent epigenetic strategy for treating neurodegeneration. To evaluate the effect of TG2 inhibition (treatment with ZDON, Boc-DON, CystamineA, and Control) in striatal cell lines from a transgenic model of Huntington disease (Q111) vs. control (Q7). One sample (WT.boc.3, 4068264015_G) failed the QC test and was excluded from further analyses.
2010-04-08 | E-GEOD-21237 | biostudies-arrayexpress
Project description:Gene Expression Profiling Using Huntington Disease Cell Culture Model and High-resolution Sp1 DNA-binding Site Mapping by ChIP-exo in STHdh Q7/Q7 cells
| PRJNA327873 | ENA
Project description:Affymetrix MG430 2.0 expression levels of wild-type (STHdhQ7/Q7), 3NP-treated wild-type (STHdhQ7/Q7NP), and mutant (STHdhQ111/Q111) striatal cells Experiment Overall Design: Investigation of HD disease mechanism by gene expression profiling of two HD model systems
2009-04-29 | E-GEOD-3583 | biostudies-arrayexpress
Project description:Deregulated intracellular Ca2+ homeostasis underlies synaptic dysfunction and is a common feature in neurodegenerative processes, including Huntington's disease (HD). DREAM/calsenilin/KChIP-3 is a multifunctional Ca2+ binding protein that controls the expression level and/or the activity of several proteins related to Ca2+ homeostasis, neuronal excitability and neuronal survival. We found that expression of endogenous DREAM (DRE antagonist modulator) is reduced in the striatum of R6 mice, in STHdh-Q111/111 knock in striatal neurons and in HD patients. DREAM down regulation in R6 striatum occurs early after birth, well before the onset of motor coordination impairment, and could be part of an endogenous mechanism of neuroprotection, since i) R6/2 mice hemizygous for the DREAM gene (R6/2xDREAM+/-) showed delayed onset of locomotor impairment and prolonged lifespan, ii) motor impairment after chronic administration of 3-NPA was reduced in DREAM knockout mice and enhanced in daDREAM transgenic mice and, iii) lentiviral-mediated DREAM expression in STHdh-Q111/111 knock in cells sensitizes them to oxidative stress. Transcriptomic analysis showed that changes in gene expression in R6/2 striatum were notably reduced in R6/2xDREAM+/- striatum. Chronic administration of repaglinide, a molecule able to bind to DREAM in vitro and to accelerate its clearance in vivo, delayed the onset of motor dysfunction, reduced striatal loss and prolonged the lifespan in R6/2 mice. Furthermore, exposure to repaglinide protected STHdh-Q111/111 knock in striatal neurons sensitized to oxidative stress by lentiviral-mediated DREAM overexpression. Thus, genetic and pharmacological evidences disclose a role for DREAM silencing in early neuroprotective mechanisms in HD.
2016-02-01 | GSE48104 | GEO
Project description:The widespread adoption of transcriptional profiling has led to immense repositories of data that may contain critical insights for developing new therapies. Current approaches to mining these data largely rely on binary classifications of disease versus control. These methods are not able to incorporate measures of disease severity, which are often available. We report an analytical approach to integrate ordinal clinical information with transcriptomics. We have applied this method to public data for a large cohort of Huntington’s disease patients and controls, identifying and prioritizing phenotype-associated genes. To validate the approach, we have performed viability, siRNA knockdown, mRNA-seq, and ChIP-seq on striatal precursor cells expressing either full-length wild type (STHdh Q7) or mutant huntingtin (STHdh Q111). We have verified the role of a high-ranked gene in dysregulation of sphingolipid metabolism in the disease and demonstrated that inhibiting the enzyme, SPL, has neuroprotective effects in HD models. We have shown that one consequence of inhibiting SPL is the intracellular inhibition of HDACs, thus linking our observations in sphingolipid metabolism to a well-characterized HD pathway. Our approach is easily applied to any data with ordinal clinical measurements, and may deepen our understanding of disease processes.
2017-05-11 | GSE98739 | GEO
Project description:The widespread adoption of transcriptional profiling has led to immense repositories of data that may contain critical insights for developing new therapies. Current approaches to mining these data largely rely on binary classifications of disease versus control. These methods are not able to incorporate measures of disease severity, which are often available. We report an analytical approach to integrate ordinal clinical information with transcriptomics. We have applied this method to public data for a large cohort of Huntington’s disease patients and controls, identifying and prioritizing phenotype-associated genes. To validate the approach, we have performed viability, siRNA knockdown, mRNA-seq, and ChIP-seq on striatal precursor cells expressing either full-length wild type (STHdh Q7) or mutant huntingtin (STHdh Q111). We have verified the role of a high-ranked gene in dysregulation of sphingolipid metabolism in the disease and demonstrated that inhibiting the enzyme, SPL, has neuroprotective effects in HD models. We have shown that one consequence of inhibiting SPL is the intracellular inhibition of HDACs, thus linking our observations in sphingolipid metabolism to a well-characterized HD pathway. Our approach is easily applied to any data with ordinal clinical measurements, and may deepen our understanding of disease processes.
2017-05-11 | GSE98738 | GEO