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Expression data in induced pluripotent stem cells (iPSCs) derived from a DNA repair deficient fibroblast

ABSTRACT: Cockayne syndrome (CS) is an autossomal human disorder characterized by premature aging along with other symptoms. At the molecular level, CS is characterized by a deficiency in the Transcription-couple DNA repair pathway caused by a mutation mainly in ERCC6 gene and the absence of its functional protein. It has been shown that the presence of DNA damage and the lack of some functional proteins related to DNA repair constitute a barrier for somatic cell reprogramming. Recently, it was demonstrated that one protein involved in Genome Global Repair controls the expression of an important pluripotent gene, highligting its importance for cellular reprogramming. We used microarray to confirm cellular reprogramming of CS fibroblasts at the molecular level and detail the expression of some genes invoved in cell death and aging control that might explain the unique characteristics of these iPSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE36648 | GEO | 2012/07/13

SECONDARY ACCESSION(S): PRJNA153655

REPOSITORIES: GEO

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Expression data in induced pluripotent stem cells (iPSCs) derived from a DNA repair deficient fibroblast

Project description:Cockayne syndrome (CS) is an autossomal human disorder characterized by premature aging along with other symptoms. At the molecular level, CS is characterized by a deficiency in the Transcription-couple DNA repair pathway caused by a mutation mainly in ERCC6 gene and the absence of its functional protein. It has been shown that the presence of DNA damage and the lack of some functional proteins related to DNA repair constitute a barrier for somatic cell reprogramming. Recently, it was demonstrated that one protein involved in Genome Global Repair controls the expression of an important pluripotent gene, highligting its importance for cellular reprogramming. We used microarray to confirm cellular reprogramming of CS fibroblasts at the molecular level and detail the expression of some genes invoved in cell death and aging control that might explain the unique characteristics of these iPSCs. Normal (wild type) and fibroblasts from a CS patient were reprogrammed and independent clones were isolated. After sucessive passages in culture, total RNA from donor fibroblasts, iPSCs clones and human embryonic stem cell line (HUES6) were isolated and transcriptional analysis using human genome Affimetrix Gene Chip arrays were performed. HUES6 was used to demonstrate that CS and normal iPSCS show a global gene expression similar to an embryonic stem cell, confirming that both fibroblasts were successfully reprogrammed. We also used fibroblasts from CS to point out the diiferences in global gene expression after reprogramming. We sought to use normal (control) iPSCs to compare the levels of some genes involved in cell death and aging in iPSCs from CS fibroblasts.

2012-07-12 | E-GEOD-36648 | biostudies-arrayexpress

Gloable gene expression is affected by loss of CSB function in the rat model for Cockayne syndrome

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

Rescue of premature aging defects in Cockayne Syndrome Derived Stem Cells by Targeted Gene Correction

Project description:Cockayne Syndrome (CS) is a rare autosomal recessive inherited disorder characterized by a variety of clinical features including sensitivity to sunlight, progressive neurological abnormalities and appearance of premature aging. However, the pathogenesis of CS yet remains unclear due to the limitations of current disease models. Here we generate integration free-induced pluripotent stem cells (iPSCs) from CS patient fibroblast bearing mutations in CSB/ERCC6 and further derive isogenic gene corrected (GC)-iPSCs using CRISPR/Cas9 system. CS cellular phenotypes are recapitulated in CS mesenchymal stem cells (MSCs) and neural stem cells (NSCs), both of which display compromised susceptibility to DNA damage stress. We next map the transcriptome landscapes of CS- and GC-iPSCs and their adult stem/progenitor cell derivatives under ultraviolet (UV) and replicative stress, indicating the defects in DNA repair in confronting the acute and chronic stress contribute to CS-disease pathology. Through RNA sequencing analysis, we also identify a panel of potential targets for treating CS. Moreover, we generate clinical GC-MSCs displaying safer and superior stem cell activity in vitro and in vivo, which may provide better cell materials for future stem cell replacement therapy in CS-disease. Our models serve to facilitate the discovery of novel disease features and molecular mechanism, as well as lay a foundation for development of novel therapeutic strategies to treat CS.

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Convergence of Cockayne Syndrome Group A and B Proteins at rRNA Transcription through Nucleolin Regulation

Project description:Cockayne Syndrome (CS) is a rare neurodegenerative disease characterized by short stature, cachexia, sun-sensitivity, accelerated aging, and short lifespan. Mutations in two human genes, ERCC8/CSA and ERCC6/CSB, are causative for CS and the protein products of these genes, CSA and CSB, while structurally unrelated, play roles in DNA repair and other aspects of DNA metabolism in human cells. Many clinical and molecular features of CS remain poorly understood, and it has been suggested that CSA and CSB regulate transcription of rDNA genes and ribosome biogenesis. The goal of this study was to investigate the dysregulation of rRNA synthesis in CS. Here, we report that Nucleolin (Ncl), a nucleolar protein that regulates rRNA synthesis and ribosome biogenesis, interacts specifically with CSA and CSB. In addition, CSA induces ubiquitination of Ncl, enhances binding of CSB to Ncl, and CSA and CSB both stimulate binding of Ncl to rDNA and subsequent rRNA synthesis. These findings suggest that CSA and CSB are positive regulators of rRNA synthesis via Ncl regulation. A majority of CS patients carry mutations in CSA and CSB and present with similar clinical features, thus our findings may provide novel insights into disease mechanism and the neuropathological features of CS.

2020-03-16 | GSE122736 | GEO

A High-Fat Diet and NAD+ Rescue Premature Aging in Cockayne Syndrome

Project description:Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in the genes encoding the DNA repair proteins CSA or CSB. Csbm/m mice were given a high-fat, caloric-restricted or resveratrol-supplemented diet. The high-fat diet rescued the phenotype of Csbm/m mice at the metabolic, transcriptomic and behavioral levels. Additional analysis suggests that the premature aging seen in CS mice, nematodes and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, β-hydroxybutyrate levels are increased by the high-fat diet; and β-hydroxybutyrate, PARP inhibition, or NAD+ supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB is able to displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, β-hydroxybutyrate and NAD+, through the deacetylase SIRT1 and suggests possible interventions for CS.

2014-12-22 | GSE62194 | GEO

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling [HumanHT-12 V4.0]

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

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling [Agilent-020186 array]

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RNA polymerase I transcription disturbances lead to instable ribosomes in Cockayne syndrome

Project description:DNA-repair factors of the Nucleotide -Excision-Repair (NER) pathway are part of the basal transcription apparatus of RNA polymerase I. Mutations in these factors can give rise to developmental disorders with symptoms that are typical for the aging body. Here we show that in Cockayne syndrome (CS) RNA polymerase I transcription elongation and the processing of the pre-rRNA are disturbed. The mature 18S rRNA is reduced and isolated ribosomes lack specific ribosomal proteins. Ribosomal proteins are susceptible to unfolding and the proteome of CS cells is heat-sensitive, indicating misfolded proteins and an error prone translation process in CS cells. Pharmaceutical chaperones restored impaired cellular proliferation. Thus, we provide evidence for severe malfunction in protein synthesis which together with a loss of proteostasis constitute the underlying pathophysiology in CS.

2021-11-16 | PXD024478 | Pride

DNA methylation of fibroblasts from Cockayne syndrome and UV-sensitivity syndrome patients [EPIC]

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.

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DNA methylation of fibroblasts from Cockayne syndrome and UV-sensitivity syndrome patients [450k]

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