Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Haj M

PROVIDER: S-EPMC10410012 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Haj Majd M Levon Amit A Frey Yann Y Hourvitz Noa N Campisi Judith J Tzfati Yehuda Y Elkon Ran R Ziv Yael Y Shiloh Yosef Y

Aging cell 20230530 8

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, the ...[more]

PMID: 37254625

Similar Datasets

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

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets