Accelerated replicative senescence of ataxia-telangiectasia skin fibroblasts is retained at physiologic oxygen levels, with unique and common transcriptional patterns.
Majd HajAmit LevonYann FreyNoa HourvitzPierre-Yves DesprezYehuda TzfatiRan ElkonYael ZivYosef ShilohPublished in: Aging cell (2023)
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.
Keyphrases
- extracellular matrix
- endothelial cells
- end stage renal disease
- genome wide
- dna damage
- rna seq
- ejection fraction
- induced apoptosis
- chronic kidney disease
- newly diagnosed
- transcription factor
- single cell
- gene expression
- protein kinase
- squamous cell carcinoma
- immune response
- peritoneal dialysis
- long non coding rna
- electronic health record
- early onset
- oxidative stress
- high glucose
- bioinformatics analysis
- single molecule
- signaling pathway
- cell death
- squamous cell
- anti inflammatory
- genome wide analysis