Epigenetic Dysregulation by Polyglutamine-expanded Ataxin-7 In The mouse model of SCA7
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE166118 | GEO | 2021/02/04
REPOSITORIES: GEO
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Project description:Transcriptional profiling of mouse cerebellar extract comparing SCA7 KI mice with wild type mice. Female mice were killed by decapitation on post natal days 10 and 22 and 11 weeks. Goal was to determine gene expression profiles differing between SCA7 KI mice and wild-type mice during post-natal developement of the cerebellum.
2013-07-24 | GSE49115 | GEO
Project description:Spinocerebellar Ataxia Type 7 (SCA7) belonging to ADCAs is pathomechanistically related to a group of polyglutamine expansion disorders. SCA7 affects primarily brainstem, retina and cerebellum. The distinctive feature of SCA7 among ADCAs is a progressive visual impairment due to a cone-rod photoreceptor dystrophy. Ultrastructural analysis of SCA7 mouse models revealed that photoreceptors progressively lose their outer segments, a structure essential for phototransduction, which requires daily renewal. The lack of outer segment renewal correlates with decreased expression of photoreceptor-specific genes, suggesting that progressive breakdown of photoreceptor cell identity accounts for SCA7 retinopathy. SCA7 is due to a polyglutamine expansion in ATXN7, a component of the multiprotein SPT-ADA-GCN5 Acetyltransferase (SAGA) complex, a highly conserved coactivator of transcription. SAGA harbors two chromatin remodeling activities: acetylation and deubiquitynation of histones crucial for transcription initiation and elongation. The role of SAGA in SCA7 pathogenesis and the tissue specific genetic breakdown remains to be elucidated. We addressed this issue using our new SCA7 knock-in mouse model (SCA7140Q/140Q), which recapitulates cardinal features of SCA7. Using ChIP-seq approach, we confirmed the general decrease of H3K9ac in most gene promoters in SCA7 retina, which alone cannot explain the specific gene deregulation. Interestingly, we discovered that photoreceptor identity genes, which are strongly downregulated in SCA7, harbor an unusual broad profile of H3K9ac that encompasses the entire gene. We further show that H3K9ac broad profiles at photoreceptor gene loci coincide with the presence of a broad H3K27ac, a signature of superenhancers. Furthermore, using vicinity criteria we identified enhancer RNAs (eRNAs), annotated to the photoreceptor identity genes possessing an atypical H3K9ac/H3K27ac enhancer signature. Finally, we found a synchronized expression of eRNAs and photoreceptor identity genes during retinal development, suggesting a regulatory role of these eRNAs. The decreased eRNA levels on hypoacetylated loci in the retina correlate with the downregulation of photoreceptor identity genes in symptomatic but not in pre-symptomatic SCA7 mice. Our results support the view that epigenetic and enhancer alterations compromise the maintenance of neuronal identity in SCA7.
2022-12-20 | GSE181323 | GEO
Project description:Spinocerebellar Ataxia Type 7 (SCA7) belonging to ADCAs is pathomechanistically related to a group of polyglutamine expansion disorders. SCA7 affects primarily brainstem, retina and cerebellum. The distinctive feature of SCA7 among ADCAs is a progressive visual impairment due to a cone-rod photoreceptor dystrophy. Ultrastructural analysis of SCA7 mouse models revealed that photoreceptors progressively lose their outer segments, a structure essential for phototransduction, which requires daily renewal. The lack of outer segment renewal correlates with decreased expression of photoreceptor-specific genes, suggesting that progressive breakdown of photoreceptor cell identity accounts for SCA7 retinopathy. SCA7 is due to a polyglutamine expansion in ATXN7, a component of the multiprotein SPT-ADA-GCN5 Acetyltransferase (SAGA) complex, a highly conserved coactivator of transcription. SAGA harbors two chromatin remodeling activities: acetylation and deubiquitynation of histones crucial for transcription initiation and elongation. The role of SAGA in SCA7 pathogenesis and the tissue specific genetic breakdown remains to be elucidated. We addressed this issue using our new SCA7 knock-in mouse model (SCA7140Q/140Q), which recapitulates cardinal features of SCA7. Using ChIP-seq approach, we confirmed the general decrease of H3K9ac in most gene promoters in SCA7 retina, which alone cannot explain the specific gene deregulation. Interestingly, we discovered that photoreceptor identity genes, which are strongly downregulated in SCA7, harbor an unusual broad profile of H3K9ac that encompasses the entire gene. We further show that H3K9ac broad profiles at photoreceptor gene loci coincide with the presence of a broad H3K27ac, a signature of superenhancers. Furthermore, using vicinity criteria we identified enhancer RNAs (eRNAs), annotated to the photoreceptor identity genes possessing an atypical H3K9ac/H3K27ac enhancer signature. Finally, we found a synchronized expression of eRNAs and photoreceptor identity genes during retinal development, suggesting a regulatory role of these eRNAs. The decreased eRNA levels on hypoacetylated loci in the retina correlate with the downregulation of photoreceptor identity genes in symptomatic but not in pre-symptomatic SCA7 mice.
2022-12-20 | GSE181324 | 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:Background Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder that primarily affects the cerebellum and retina. SCA7 is caused by a polyglutamine expansion in the ATXN7 protein, a subunit of the transcriptional coactivator SAGA that acetylates histone H3 to deposit narrow H3K9ac mark at DNA regulatory elements of active genes. Defective histone acetylation has been presented as a possible cause for gene deregulation in SCA7 mouse models. However, the topography of acetylation defects at the whole genome level and its relationship to changes in gene expression remain to be determined. Methods We performed deep RNA-sequencing and chromatin immunoprecipitation coupled to high-throughput sequencing to examine the genome-wide correlation between gene deregulation and alteration of the active transcription marks, e.g. SAGA-related H3K9ac, CBP-related H3K27ac and RNA polymerase II (RNAPII), in a SCA7 mouse retinopathy model. Results Our analyses revealed that active transcription marks are reduced at most gene promoters in SCA7 retina, while a limited number of genes show changes in expression. We found that SCA7 retinopathy is caused by preferential downregulation of hundreds of highly expressed genes that define morphological and physiological identities of mature photoreceptors. We further uncovered that these photoreceptor genes harbor unusually broad H3K9ac profiles spanning the entire gene bodies and have a low RNAPII pausing. This broad H3K9ac signature co-occurs with other features that delineate superenhancers, including broad H3K27ac, binding sites for photoreceptor specific transcription factors and expression of enhancer-related non-coding RNAs (eRNAs). In SCA7 retina, downregulated photoreceptor genes show decreased H3K9 and H3K27 acetylation and eRNA expression as well as increased RNAPII pausing, suggesting that superenhancer-related features are altered. Conclusions Our study thus provides evidence that distinctive epigenetic configurations underlying high expression of cell-type specific genes are preferentially impaired in SCA7, resulting in a defect in the maintenance of identity features of mature photoreceptors. Our results also suggest that continuous SAGA-driven acetylation plays a role in preserving post-mitotic neuronal identity.
2022-12-20 | GSE181325 | GEO
Project description:Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination due to progressive cerebellar degeneration. SCA7 is caused by polyglutamine expansion in ATXN7, a subunit of the transcriptional coactivator SAGA, which harbors histone modification activities. Polyglutamine expansions in specific proteins are also responsible for SCA1-3, 6 and 17, however, the converging and diverging pathomechanisms remain poorly understood. Using a new SCA7 knock-in mouse, SCA7140Q/5Q, we analyzed gene expression in the cerebellum and assigned gene deregulation to specific cell types using published datasets. Gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks. Purkinje cells (PCs) are by far the most affected neurons and show reduced expression of 83 cell-type identity genes, including these critical for their spontaneous firing activity and synaptic functions. PC gene downregulation precedes morphological alterations, pacemaker dysfunction and motor incoordination. Strikingly, most PC genes downregulated in SCA7 have also decreased expression in SCA1 and SCA2 mice, revealing converging pathomechanisms and a common disease signature involving cGMP-PKG and phosphatidylinositol signaling pathways and long-term depression. Our study thus points out molecular targets for therapeutic development, which may prove beneficial for several SCAs. Furthermore, we show that SCA7140Q/5Q males and females exhibit the major disease features observed in patients, including cerebellar damage, cerebral atrophy, peripheral nerves pathology and photoreceptor dystrophy, which account for progressive impairment of behavior, motor and visual functions. SCA7140Q/5Q mice represent an accurate model for the investigation of different aspects of SCA7.
2021-04-26 | GSE138527 | GEO
Project description:Transcriptional profiling of mouse cerebellar extract comparing SCA7 KI mice with wild type mice. Female mice were killed by decapitation on post natal days 10 and 22 and 11 weeks. Goal was to determine gene expression profiles differing between SCA7 KI mice and wild-type mice during post-natal developement of the cerebellum. Gene expression profiling was performed using RNA extracted from the cerebellum of KI and WT mice at P10 (5 WT and 5 KI), P22 (5 WT and 4 KI) and 11 wks (5WT and 6 KI). After labeling, RNAs were hybridized on dual-label G4122F AgilentM-BM-. chips; a mix of all P10 samples was used as common reference (green channel). Quality control included visual control of the reconstructed image of the chip, M/A plot, corner intensities, outliers, positive and negative intensities, normalization factors. Normalization and statistical analyses were carried out by using BRB-array Tools developed by Dr. Richard Simon and the BRB-ArrayTools development team (Biometrics Research Branch, http://linus.nci.nih.gov/BRB-ArrayTools.html). Genes with less than 50% present calls or with low variability along the arrays (less than 20% of values with at least 2-fold change in either direction from the geneM-bM-^@M-^Ys median value) were excluded from further analysis. For the 1905 remaining probes an interaction between time and genotype was analyzed by regression analysis of the time course of expression. In brief, probes for which variation over time differed for the genotype class were fitted to the following model: log expression ~ time + time**2 + genotype + genotype*time + genotype*time**2. A univiariate p-value < 0.001 (random variance model) was set for significant probes (genotype*time + genotype*time**2) and a False Discovery Rate (FDR) was calculated for each probe (Benjamini & Hochberg, 1995). Differences in profiles were identified with a Self Organisation Tree Algorithm (MultiplExperiment Viewer (MeV), (Saeed et al, 2006). Expression values were averaged by group and then clustered according to their profile as a function of time.
2013-07-24 | E-GEOD-49115 | biostudies-arrayexpress
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:Comparative analysis of cerebellar gene expression changes occurring in Sca1154Q/2Q and Sca7266Q/5Q knock-in mice Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG repeats encoding a glutamine tract in the disease-causing proteins. There are nine disorders each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and type 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with degeneration of Purkinje cells. To determine whether the disorders share molecular pathogenic events, we studied two mouse models of SCA1 and SCA7 that express the glutamine-expanded protein from the respective endogenous loci. We found common transcriptional changes, with down-regulation of Insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust changes. Igfbp5 down-regulation occurred in granule neurons through a non-cell autonomous mechanism and was concomitant with activation of of the Insulin-like growth factor (IGF) pathway and the type I IGF receptor on Purkinje cells. These data define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular mechanisms in their pathogenesis. Given that SCA1 and SCA7 share a cerebellar degenerative phenotype, we proposed that some shared molecular changes might occur in both diseases, and that common molecular alterations could pinpoint pathways that could be targeted to modulate or monitor the pathogenesis of more than one disease. We focused on transcriptional changes because both ATXN1 and ATXN7 play roles in transcriptional regulation and transcriptional defects can be detected in early-symptomatic stages of both SCA1 and SCA7 mouse models. To test our hypothesis, we examined cerebellar gene expression patterns in SCA1 and SCA7 knock-in (KI) models--Sca1154Q/2Q and Sca7266Q/5Q mice. Keywords: comparative disesae state analysis between Sca1154Q/2Q and Sca7266Q/5Q knock-in cerebellum
2007-12-18 | GSE9914 | GEO
Project description:RNA-seq analysis of the cerebellum of SCA7 mice treated with AAV expressing shRNA targeting Atxn7
| PRJNA1026540 | ENA