Transcriptomics

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Accelerated replicative senescence of ataxia-telangiectasia skin fibroblasts is retained at physiologic oxygen levels, with unique and common transcriptional patterns


ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE182410 | GEO | 2023/05/09

REPOSITORIES: GEO

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