Accelerated replicative senescence of ataxia-telangiectasia skin fibroblasts is retained at physiologic oxygen levels, with unique and common transcriptional patterns
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ABSTRACT:
PROVIDER: PRJNA756191 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15525900_1.fastq.gz | Fastqsanger.gz | |||
| SRR15525900_2.fastq.gz | Fastqsanger.gz | |||
| SRR15525901_1.fastq.gz | Fastqsanger.gz | |||
| SRR15525901_2.fastq.gz | Fastqsanger.gz | |||
| SRR15525902_1.fastq.gz | Fastqsanger.gz |
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Project description:Genome instability enhances the pace of aging. Therefore, genome instability syndromes are usually associated with accelerated segmental aging. Genome integrity in the face of ongoing DNA damage is maintained primarily by the DNA damage response (DDR) – a complex signaling network that is induced by DNA lesions. Among the strongest DDR inducers are double-strand breaks (DSBs) – extremely cytotoxic lesions. The chief mobilizer of the DSB response is the ATM protein kinase. ATM loss in humans leads to a multisystem genome instability syndrome, ataxia-telangiectasia (A-T). Part of the complex A-T phenotype is segmental premature aging. Cellular senescence is a cell fate that includes cell cycle arrest, marked alterations in chromatin organization and metabolic circuits, and a multi-faceted senescence-associated secretory phenotype (SASP). This process plays a role in development and tissue homeostasis, as well as age-related degenerative and malignant diseases. Senescent cells increase with age in all tissues studied, and consequently, the SASP can disrupt the tissue microenvironment. Early studies demonstrated a rapid decline in the proliferation of cultured primary skin fibroblasts from A-T patients, which was attributed to premature senescence. Comparative RNA-sequencing analysis of A-T and control fibroblasts revealed unique transcriptional alterations in A-T cells and their dynamics over time in culture. Cluster analysis of differentially expressed genes (DEGs) allowed for the detection and categorization of these transcriptomic patterns. Functional enrichment analyses provided insight into the molecular pathways and cellular components associated with the premature senescence of A-T cells. The results were further corroborated by analyzing alterations in gene expression profiles using ‘gene set enrichment analysis’ (GSEA). Altogether, the analyses point to engagement of interferon signaling and extracellular matrix remodeling pathways, which are presumably caused by an accumulation of DNA damage. Notably, these pathways are known to be involved in cellular senescence and various age-related pathologies, including fibrosis and cancer. Our data provide a molecular dimension to the segmental premature aging observed in A-T patients
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Project description:The genetic disorder, ataxia-telangiectasia (A-T), is caused by loss of the homeostatic protein kinase, ATM, and combines genome instability, tissue degeneration, cancer predisposition, and premature aging. Primary fibroblasts from A-T patients exhibit premature senescence when grown at ambient oxygen concentration (21%). Here, we show that reducing oxygen concentration to a physiological level range (3%) dramatically extends the proliferative lifespan of human A-T skin fibroblasts. However, they still undergo senescence earlier than control cells grown under the same conditions and exhibit high genome instability. Comparative RNA-seq analysis of A-T and control fibroblasts cultured at 3% oxygen followed by cluster analysis of differentially expressed genes and functional enrichment analysis, revealed distinct transcriptional dynamics in A-T fibroblasts senescing in physiological oxygen concentration. While some transcriptional patterns were similar to those observed during replicative senescence of control cells, others were unique to the senescing A-T cells. We observed in them a robust activation of interferon-stimulated genes, with undetected expression the interferon genes themselves. This finding suggests an activation of a non-canonical cGAS-STING-mediated pathway, which presumably responds to cytosolic DNA emanating from extranuclear micronuclei detected in these cells. Senescing A-T fibroblasts also exhibited a marked, intriguely complex alteration in the expression of genes associated with extracellular matrix (ECM) remodeling. Notably, many of the induced ECM genes encode senescence-associated secretory phenotype (SASP) factors known for their paracrine pro-fibrotic effects. Our data provide a molecular dimension to the segmental premature aging observed in A-T patients and its associated symptoms, which develop as the patients advance in age.
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Project description:Cerebellar cortex expression in ataxia-telangiectasia patients and normal controls. The neurodegenerative disease known as ataxia-telangiectasia (A-T) is caused by the absence of the ATM (A-T mutated) protein. A long-standing mystery surrounding A-T is why cerebellar Purkinje cells (PCs) appear uniquely vulnerable to ATM-deficiency. Here, we present that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human A-T and Atm-/- mouse cerebellar PCs. TET1, an enzyme that converts 5mC to 5hmC, responds to DNA damage. Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage. Quantitative, genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements. These results reveal a role of TET1-mediated 5hmC in DNA damage response, and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency. Human frozen tissue was obtained from the NICHD Brain and Tissue Bank of Developmental Disorders at the University of Maryland, Baltimore, MD. RNA was prepared and run on an Illumina Human HT-12 v4 microarray. 3 ataxia-telangiectasia (A-T) cases and 4 normal controls.
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Project description:Disease-specific induced pluripotent stem (iPS) cells have been used for a model to analyze pathogenesis of the disease. In this study, we generated iPS cells derived from a fibroblastic cell line of ataxia telangiectasia (AT-iPS cells), a neurodegenerative, inherited disease with chromosomal instability and hypersensitivity to ionizing radiation. AT-iPS cells exhibited hypersensitivity to X-ray irradiation, one of the characteristics of the disease. Surprisingly, while parental ataxia telangiectasia cells exhibited significant chromosomal abnormalities, AT-iPS cells did not show any chromosomal instability in vitro, i.e. maintenance of intact chromosomes at least by 80 passages (560 days) probably due to robust stability of pluripotent stem cells such as iPS cells and embryonic stem cells. The whole exome analysis also showed comparable nucleotide substitution speed in AT-iPS cells. Interestingly, after longer period of AT-iPS implantation into immunodeficient mice, teratoma generated by AT-iPS cells exhibited telangiectasia and carcinogenesis that are two characteristic symptoms of ataxia telangiectasia. Taken together, AT-iPS cells would be a good model for ataxia telangiectasia to clarify pathogenesis of the disease, and may allow us to facilitate development of drugs that inhibit ataxia and hypersensitivity to ionizing radiation for therapeutic application.
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Project description:Disease-specific induced pluripotent stem (iPS) cells have been used for a model to analyze pathogenesis of the disease. In this study, we generated iPS cells derived from a fibroblastic cell line of ataxia telangiectasia (AT-iPS cells), a neurodegenerative, inherited disease with chromosomal instability and hypersensitivity to ionizing radiation. AT-iPS cells exhibited hypersensitivity to X-ray irradiation, one of the characteristics of the disease. Surprisingly, while parental ataxia telangiectasia cells exhibited significant chromosomal abnormalities, AT-iPS cells did not show any chromosomal instability in vitro, i.e. maintenance of intact chromosomes at least by 80 passages (560 days) probably due to robust stability of pluripotent stem cells such as iPS cells and embryonic stem cells. The whole exome analysis also showed comparable nucleotide substitution speed in AT-iPS cells. Interestingly, after longer period of AT-iPS implantation into immunodeficient mice, teratoma generated by AT-iPS cells exhibited telangiectasia and carcinogenesis that are two characteristic symptoms of ataxia telangiectasia. Taken together, AT-iPS cells would be a good model for ataxia telangiectasia to clarify pathogenesis of the disease, and may allow us to facilitate development of drugs that inhibit ataxia and hypersensitivity to ionizing radiation for therapeutic application. The parental AT1OS fibroblast cells and four independent AT-iPS clones were subjected to Illumina HumanCytoSNP-12 v2.1 BeadChip analysis.
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