Cockayne syndrome (CSB) fibroblasts
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE3407 | GEO | 2006/07/14
SECONDARY ACCESSION(S): PRJNA93425
REPOSITORIES: GEO
Similar Datasets
Project description:Cockayne syndrome (CS) is an inherited neurodevelopmental disorder with progeroid features. Although the genes responsible for CS have been implicated in a variety of DNA repair- and transcription-related pathways, the nature of the molecular defect in CS remains mysterious. We sought to define this defect by expression analysis of cells lacking functional CSB, a SWI/SNF-like ATPase that is responsible for most CS cases.
2007-07-03 | E-GEOD-3407 | biostudies-arrayexpress
Project description:Cockayne syndrome (CS) is a rare genetic neurodevelopmental disorder, characterized by a deficiency in the transcription-coupled nucleotide excision repair pathway. Mutation of Cockayne syndrome B (CSB) affects basal transcription which is considered a major cause of CS neurological dysfunction. Here, we generated a rat model by mimicking a nonsense mutation in the CSB(ERCC6) gene of CS-B patients. CSB-deficient rats exhibit the well-known CS repair characteristics: inability to resume RNA synthesis from stalled RNA polymerase II (RNAP II) and persistent gamma H2AX overexpression after UV damage. In contrast to that of the Csb-/- mouse models, the cerebella of the CSB-deficient rats are more profoundly affected. Both the molecular and the granular layers of the cerebellum cortex showed significant atrophy. The white matter of the cerebellum demonstrated high GFAP staining indicative of reactive astrogliosis. RNA-seq analysis of CSB-deficient rat cerebella revealed that even in the absence of UV damage, CSB affects the expression of hundreds of genes, many of which are neuronal genes, suggesting that transcription dysregulation could contribute to the neurological features in CSB rat models.
2019-02-05 | GSE126032 | GEO
Project description:Cockayne syndrome (CS) is a rare genetic disorder caused by mutation of the DNA repair and chromatin remodelling proteins CSA or CSB. Increasing evidences indicate that the progeroid phenotype of CS cannot be solely ascribed to impaired DNA repair, and UV-sensitivity syndrome (UVSS) patients that are also mutated for CSA or CSB do not age prematurely. Epigenetic modifications constitute a hallmark of ageing. We assessed genome-wide DNA methylation (DNAm) at single-nucleotide resolution on fibroblasts derived from CS versus UVSS patients and healthy donors.
2023-12-24 | GSE163840 | GEO
Project description:Cockayne syndrome (CS) is a rare genetic disorder caused by mutation of the DNA repair and chromatin remodelling proteins CSA or CSB. Increasing evidences indicate that the progeroid phenotype of CS cannot be solely ascribed to impaired DNA repair, and UV-sensitivity syndrome (UVSS) patients that are also mutated for CSA or CSB do not age prematurely. Epigenetic modifications constitute a hallmark of ageing. We assessed genome-wide DNA methylation (DNAm) at single-nucleotide resolution on fibroblasts derived from CS versus UVSS patients and healthy donors.
2023-12-24 | GSE163839 | GEO
Project description:Mutations in the CSA and CSB genes are causative of Cockayne syndrome neurological disorder. Since the identification of the indispensable functions of these two proteins in transcription-coupled repair and restoring RNA synthesis following DNA damage, the paradoxical milder clinical spectrum in CS-A patients has been puzzling. In this study we compared the effect of a CSA and a CSB defect at the levels of the cell and the intact organism. We showed that CSA-deficient zebrafish embryos exhibited modest hypersensitive to UV damage than CSB depletion. We found that loss of CSA can effectively release aggregation of mutant crystallin proteins in vitro. We described the distinct effect of CSA and CSB on neuritogenesis and elucidated the differentiated gene expression pathways regulated by these two proteins. Our data demonstrate convergent and divergent roles for CSA and CSB in DNA repair and transcription regulation and provide explanations for the reported differences between CS-A and CS-B patients.
2019-03-29 | GSE129002 | GEO
Project description:Cockayne syndrome B (CSB) protein is a member of the SWI/SNF family and has DNA-dependent ATPase and ATP-dependent chromatin remodeling activities. The CSB protein is missing or altered in CS-B cells. CS-B cells are hypersensitive to UV light and defective in transcription-coupled DNA repair (TCR). TCR efficiently removes a variety of lesions from the transcribed strand of active genes. It has been shown that lesions specifically in the transcribed strand of active genes trigger the induction of apoptosis following UV irradiation. Several DNA damage signaling cascades, including the ATR/Chk1, p38 kinase, p53, and jun N-terminal kinase pathways are activated following UV irradiation. However, the role of TCR in cellular global transcriptional responses to UV irradiation remains to be elucidated. Using oligonucleotide microarray technology, we analyzed the time course of responses of CS-B cells (CS-B) and CS-B cells complemented with wild-type CSB cDNA (CS-B wt). Experiment Overall Design: In order to investigate the global transcriptional responses to UV damage in TCR-proficient or TCR-deficient cells, CS-B wt and CS-B cells were irradiated with 10 J/m2 of UV light and incubated for 2 or 12 hours. All experiments were performed in triplicate.
2008-06-17 | E-GEOD-8939 | biostudies-arrayexpress
Project description:Cockayne syndrome (CS) is a rare premature aging disease, which in the majority of cases is caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and die by 12 years of age on average. The CS proteins are involved in transcription and DNA repair, including a specialized form of DNA repair called transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, likely contributing to the severe premature aging phenotype of this disease. Our cross-species transciptomic analysis in CS postmortem brain tissue, CS mouse and C. elegans models showed that mitochondrial dysfunction is indeed a common feature in CS. Interestingly, the restoration of mitochondrial dysfunction through NAD+ supplementation significantly improved lifespan and healthspan in the C. elegans models of CS, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. We proceeded to perform molecular studies on cerebellar samples obtained from CS patients. We found that these patients exhibited molecular signatures of dysfunctional mitochondrial dynamics that can be corrected with NAD+ supplementation in primary cells with depleted CSA or CSB. Our study provides support for the interconnection between two major aging theories, DNA damage and mitochondrial dysfunction. Together these two agents contribute to an accelerated aging program that can be averted by NAD+ supplementation.
2020-12-22 | GSE144557 | GEO
Project description:Cockayne syndrome (CS) is a rare premature aging disease, which in the majority of cases is caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and die by 12 years of age on average. The CS proteins are involved in transcription and DNA repair, including a specialized form of DNA repair called transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, likely contributing to the severe premature aging phenotype of this disease. Our cross-species transciptomic analysis in CS postmortem brain tissue, CS mouse and C. elegans models showed that mitochondrial dysfunction is indeed a common feature in CS. Interestingly, the restoration of mitochondrial dysfunction through NAD+ supplementation significantly improved lifespan and healthspan in the C. elegans models of CS, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. We proceeded to perform molecular studies on cerebellar samples obtained from CS patients. We found that these patients exhibited molecular signatures of dysfunctional mitochondrial dynamics that can be corrected with NAD+ supplementation in primary cells with depleted CSA or CSB. Our study provides support for the interconnection between two major aging theories, DNA damage and mitochondrial dysfunction. Together these two agents contribute to an accelerated aging program that can be averted by NAD+ supplementation.
2020-12-22 | GSE144556 | GEO
Project description:Cockayne syndrome is a segmental progeria most often caused by mutations in the CSB gene encoding a SWI/SNF-like ATPase required for transcription-coupled DNA repair (TCR). Over 43 Mya before marmosets diverged from humans, a piggyBac3 (PGBD3) transposable element integrated into intron 5 of the CSB gene. As a result, primate CSB genes now generate both CSB protein and a conserved CSB-PGBD3 fusion protein in which the first 5 exons of CSB are alternatively spliced to the PGBD3 transposase. We show by microarray analysis that expression of the fusion protein alone in CSB-null UV-sensitive syndrome cells (UVSS1KO) cells induces an interferon-like response that resembles both the innate antiviral response and the prolonged interferon response normally maintained by unphosphorylated STAT1 (U-STAT1); moreover, as might be expected based on conservation of the fusion protein, this potentially cytotoxic interferon-like response is largely reversed by coexpression of functional CSB protein. Interestingly, expression of CSB and the CSB-PGBD3 fusion protein together, but neither alone, upregulates the insulin growth factor binding protein IGFBP5 and downregulates IGFBP7, suggesting that the fusion protein may also confer a metabolic advantage, perhaps in the presence of DNA damage. Finally, we show that the fusion protein binds in vitro to members of a dispersed family of 900 internally deleted piggyBac elements known as MER85s, providing a potential mechanism by which the fusion protein could exert widespread effects on gene expression. Our data suggest that the CSB-PGBD3 fusion protein is important in both health and disease, and could play a role in Cockayne syndrome. 12 samples total; 4 gene expression conditions in triplicate; 1 condition is a tag-only negative control
2014-03-20 | E-GEOD-56049 | biostudies-arrayexpress
Project description:Cockayne syndrome (CS) is a severe disorder with no effective treatment. The Cockayne syndrome group B (CSB) gene is one gene responsible for CS and also causes UV sensitive syndrome (UVSS), a disorder that causes mild symptoms. How the CSB gene determines a patient’s fate is unknown, but one intriguing point is that in UVSS patient cell, there are nonsense mutations in both alleles at the same position in each upstream region of the PiggyBac transposable element derived 3 (PGBD3) inserted region. In contrast, in CS patient cells, there is at least one allele with several mutations downstream of the PGBD3 inserted region, or there are homozygous mutations in exon 1. Here, we designed and synthesized 24 splice switching oligonucleotides (SSOs) to skip exon 3 in CSB mRNA. Use of these SSOs induced a frame shift in order to generate an alternative stop codon at the upstream region of the PGBD3 invasion site. As a result, a reduction of mitochondrial membrane potential following H2O2 treatment in CS cell was recovered. It was demonstrated that up-regulation of several gene expression brought about by SSOs are related to mitochondrial dysfunction in CS cells.
2018-04-09 | GSE111989 | GEO