Epigenetic Dysregulation by Polyglutamine-expanded Ataxin-7 In The mouse model of SCA7
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA699289 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13622065.fastq.gz | Fastqsanger.gz | |||
| SRR13622066.fastq.gz | Fastqsanger.gz | |||
| SRR13622067.fastq.gz | Fastqsanger.gz | |||
| SRR13622068.fastq.gz | Fastqsanger.gz | |||
| SRR13622069.fastq.gz | Fastqsanger.gz |
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Project description:To determine if STAGA complex dysfunction affects chromatin remodeling in SCA7 cerebellar degeneration, we pursued unbiased ChIP-Seq analysis of histone 3 lysine 9 acetylation (H3K9ac), as this histone mark is an established indicator of open chromatin in the transcription regulatory regions of most genes. We studied SCA7 266Q knock-in mice which faithfully recapitulate a severe, rapidly progressive neurodegenerative phenotype involving the cerebellum. We detected altered H3K9ac in the promoter regions of 777 genes in the cerebellum of SCA7 266Q knock-in mice and wild-type littermate control mice, and noted that the vast majority of these chromatin alterations corresponded to markedly increased H3K9 promoter acetylation in genes expressed in the cerebellum of SCA7 model mice.
2021-02-04 | GSE166118 | GEO
Project description:To determine whether a predisposition to DNA damage exists in SCA7 and how extensive the predilection to DNA damage might be in SCA7, we used LAM-HTGTS, a powerful high throughput next generation sequencing technique developed for monitoring of DNA double-strand break formation. We modified the LAM-HTGTS protocol by utilizing CRISPR-Cas9 to create the double-strand DNA break at a specific site and also added a step with a 5’ methyl cytosine modified primer to promote LpnPI endonuclease cleavage of sealed breaks to enrich for translocation events. Our unbiased native chromosome DNA repair experimentation revealed that expression of polyglutamine-expanded ataxin-7 yielded greatly reduced translocations in comparison to normal ataxin-7, which is consistent with retained canonical NHEJ repair, decreased HDR activity, and decreased SSA repair in SCA7 cells, as the classical NHEJ pathway is known to prevent translocation by ligating broken double-strand breaks.
2021-02-04 | GSE166119 | GEO
Project description:Spinocerebellar ataxia type 7 (SCA7) is a genetic neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. Purkinje cells (PCs) are central to the pathology of ataxias, but their low abundance in the cerebellum underrepresents their transcriptomes in sequencing assays. To address this issue, we developed a PC enrichment protocol and sequenced individual nuclei from mice and patients with SCA7. Single-nucleus RNA sequencing in SCA7-266Q mice revealed dysregulation of cell identity genes affecting glia and PCs. Specifically, genes marking zebrin-II PC subtypes accounted for the highest proportion of DEGs in symptomatic SCA7-266Q mice. These transcriptomic changes in SCA7-266Q mice were associated with increased numbers of inhibitory synapses as quantified by immunohistochemistry and reduced spiking of PCs in acute brain slices. Dysregulation of zebrin-II cell subtypes was the predominant signal in PCs of SCA7-266Q mice and was associated with the loss of zebrin-II striping in the cerebellum at motor symptom onset. We furthermore demonstrated zebrin-II stripe degradation in additional mouse models of polyglutamine ataxia and observed decreased zebrin-II expression in the cerebella of patients with SCA7. Our results suggest that a breakdown of zebrin subtype regulation is a shared pathological feature of polyglutamine ataxias.
2024-08-14 | GSE269430 | GEO
Project description:Spinocerebellar ataxia type 7 (SCA7) belonging to a family of autosomal dominant cerebellar ataxias (ADCAs) is pathomechanistically associated with the group of polyglutamine expansion disorders which include SCA 1-3, 6, 7 and 17, and Huntington’s disease. These rare diseases share a common mutational feature that is the expansion of CAG repeat sequence in disease causing genes. These mutations lead to neuronal accumulation of expanded polyglutamine proteins and selective patterns of neurodegeneration. SCA7 is caused by a polyglutamine expansion in ATAXIN-7 (ATXN7), a subcomponent of co-activatory transcriptional complex SAGA and primarily affects the cerebellum, retina and brainstem. Currently, only treatments alleviating symptoms are available to patients. Allele-selective lowering of mutant polyQ proteins promises to have high therapeutic outcomes and safety profiles. In this study, PhP.eB adeno-associated virus (AAV PhP.eB) was used to deliver several shRNAs targeting expanded CAG repeats that were tested for their safety and efficacy to lower the mATXN7 level in the brain. The SCA7140Q/5Q knock-in mice that expresses a mutated Atxn7 allele harboring an expansion of 140 CAG triplet repeats and the wild type mouse allele with 5 CAGs were used in the study. Our SCA7 140Q/5Q KI mouse model remarkably recapitulates cardinal features of SCA7 and bears the potential for pre-clinical trials (Niewiadomska-Cimicka et al., J.Neurosci., 2021). We showed that systemic injection of the AAV-shA4, the most allele-selective and safe reagent of our collection, results in improvement of motor phenotypes as indicated in open field test, and partial correction of transcriptional alterations in the cerebellum of SCA7 mice.
2024-05-14 | GSE244970 | GEO
Project description:Spinocerebellar ataxia type 1 (SCA1) is caused by a polyglutamine expansion in the ATXN1 gene leading to an expanded polyglutamine tract in the ATAXIN-1 protein. Ataxin-1 is broadly expressed throughout the brain and is known to be involved in regulating gene expression; however, it is not yet determined if mutant ataxin-1 regulates alternative splicing events. Utilizing SCA1 mouse models, we performed bulk RNA sequencing and looked for misregulated alternative splicing (mAS) events in SCA1 mouse cerebella. We found that mutant ataxin-1 causes mAS events to occur in the SCA1 mouse cerebella. Furthermore, we showed that abnormal splicing events predominantly occur in cell types that express mutant ataxin-1. Less than 25% of the mAS events were also differentially expressed genes (DEGs) and therefore their transcriptional dysregulation was previously unknown in the context of SCA1. We show through gene ontology analysis that mAS events reveal new biological pathways: mAS events showed changes in structural morphogenesis whereas DEGs showed changes in ion channel and transmembrane transport. We also report that mutant ataxin-1 causes dysregulation of expression of other ataxia-causing genes, providing evidence for molecular basis of clinical similarity among otherwise heterogeneous inherited cerebellar ataxias. We also identified the potential mechanism by which mutant ATXN1 causes mAS through its interaction with RBFOX1.
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Project description:This SuperSeries is composed of the following subset Series: GSE38000: Polyglutamine expanded huntingtin dramatically alters the genome-wide binding of HSF1 (ChIP-Seq) GSE38001: Polyglutamine expanded huntingtin dramatically alters the genome-wide binding of HSF1 (mRNA) Refer to individual Series
2012-06-18 | E-GEOD-38002 | biostudies-arrayexpress
Project description:Spinocerebellar ataxia type-1 is caused by an abnormally expanded polyglutamine (polyQ) tract in ataxin-1 protein. These expansions are responsible for protein misfolding and self-assembly into intranuclear inclusion bodies (IIBs) that are linked to neuronal death. Here, we describe a nuclear protein aggregation model of pathogenic human ataxin-1. Using an inducible Sleeping Beauty transposon system, we overexpressed ATXN1Q82 gene in human mesenchymal stem cells that are resistant to the early cytotoxic effects of the mutant protein. We characterized the structure and the protein composition of insoluble polyQ IIBs which gradually occupy the nuclei. In response to their formation, our transcriptome analysis reveals a cerebellum-specific perturbed protein interaction network, primarily affecting protein translation. Our study resolves the previously unknown architecture of insoluble polyQ IIBs and suggests that they affect the assembly and the function of the ribosome. Our inducible cell system faithfully models a human cerebellum at the end-stage of the disease.
2020-02-18 | PXD012709 | Pride
Project description:Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder that results from polyglutamine expansion of the ataxin-7 (ATXN7) protein. Remarkably, although mutant ATXN7 is expressed throughout the body, pathology is restricted primarily to the cerebellum and retina. One major goal has been to identify factors that contribute to the tissue specificity of SCA7. Here we describe the development and use of a human astrocyte cell culture model to identify reelin, a factor intimately involved in the development and maintenance of Purkinje cells and the cerebellum as a whole, as an ATXN7 target gene. We found that polyglutamine expansion decreased ATXN7 occupancy, which correlated with increased levels of histone H2B monoubiquitination, at the reelin promoter. Treatment with trichostatin A, but not other histone deacetylase inhibitors, partially restored reelin transcription and promoted the accumulation of mutant ATXN7 into nuclear inclusions. Our findings suggest that reelin could be a previously unknown factor involved in the tissue specificity of SCA7 and that trichostatin A may ameliorate deleterious effects of the mutant ATXN7 protein by promoting its sequestration away from promoters into nuclear inclusions.
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Project description:Ataxin 1 (Atxn1) is a protein of unknown function associated with cerebellar neurodegeneration in spinocerebellar ataxia type 1 (SCA1). SCA1 is caused by an expanded polyglutamine within Atxn1 by gain-of-function mechanisms. Lack of Atxn1 in mice triggers motor deficits in the absence of neurodegeneration or apparent neuropathological abnormalities.We extracted RNA from cerebellum of 5 Atxn1-null mice and 5 WT. Cerebellar gene expression profiles at 15 weeks of age were generated usSCA1 ing Affymetrix MOE430A arrays. Identifying the molecular pathways regulated by Atxn1 can provide insights into the early molecular mechanisms underlying neuronal dysfunction.
2006-12-01 | E-MEXP-886 | biostudies-arrayexpress
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