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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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Project description:Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces Ã¢Â?Â?SASP-likeÃ¢Â?Â? inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression. This study examines the genome-wide distribution of gH2A.x and H3K4me3 by chIP-seq, using input and whole histone subunit H3 (respectively) as controls for local sonication efficiency bias. Each of the four chIPs has a single replicate each in (i) IMR90 fibroblasts transfected with a scramble control vector, (ii) the same cells subject to oncogene-induced senescence by stimulation of H-Ras V12, and (iii) in OIS cells with a shRNA targeting MLL1. Additionally, gH2A.x and input were sequenced with another replicate in control and OIS cells (both scramble control).

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

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