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Implications of time-series gene expression profiles of replicative senescence

ABSTRACT: Although senescence has long been implicated in aging-associated pathologies, it is not clearly understood how senescent cells are linked to these diseases. To address this knowledge gap, we profiled cellular senescence phenotypes and mRNA expression patterns during replicative senescence in human diploid fibroblasts. We identified a sequential order of gain-of-senescence phenotypes: low levels of reactive oxygen species, cell mass/size increases with delayed cell growth, high levels of reactive oxygen species with increases in senescence-associated β-galactosidase activity (SA-β-gal), and high levels of SA-β-gal activity. Gene expression profiling revealed four distinct modules in which genes were prominently expressed at certain stages of senescence, allowing us to divide the process into four stages: early, middle, advanced, and very advanced. Interestingly, the gene expression modules governing each stage supported the development of the associated senescence phenotypes. Senescence-associated secretory phenotype-related genes also displayed a stage-specific expression pattern with three unique features during senescence: differential expression of interleukin isoforms, differential expression of interleukins and their receptors, and differential expression of matrix metalloproteinases and their inhibitory proteins.

ORGANISM(S): Homo sapiens

PROVIDER: GSE41714 | GEO | 2013/04/24

SECONDARY ACCESSION(S): PRJNA178010

REPOSITORIES: GEO

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Implications of time-series gene expression profiles of replicative senescence

Project description:Although senescence has long been implicated in aging-associated pathologies, it is not clearly understood how senescent cells are linked to these diseases. To address this knowledge gap, we profiled cellular senescence phenotypes and mRNA expression patterns during replicative senescence in human diploid fibroblasts. We identified a sequential order of gain-of-senescence phenotypes: low levels of reactive oxygen species, cell mass/size increases with delayed cell growth, high levels of reactive oxygen species with increases in senescence-associated M-NM-2-galactosidase activity (SA-M-NM-2-gal), and high levels of SA-M-NM-2-gal activity. Gene expression profiling revealed four distinct modules in which genes were prominently expressed at certain stages of senescence, allowing us to divide the process into four stages: early, middle, advanced, and very advanced. Interestingly, the gene expression modules governing each stage supported the development of the associated senescence phenotypes. Senescence-associated secretory phenotype-related genes also displayed a stage-specific expression pattern with three unique features during senescence: differential expression of interleukin isoforms, differential expression of interleukins and their receptors, and differential expression of matrix metalloproteinases and their inhibitory proteins. The analysis of time series gene expression level during replicaive senescence.

2013-04-24 | E-GEOD-41714 | biostudies-arrayexpress

Chemotherapy-induced cellular senescence is characterized by aberrant lipid regulation and lipid peroxidation

Project description:As normal cells approach their proliferative limit, they arrest to undergo replicative senescence, displaying large cell size, flat morphology and activation of senescence-associated beta-galactosidase (SA-b-Gal). A subset of normal or tumor cells exposed in vitro or in vivo to chemotherapy agents such as etoposide perform a related response with a similar cellular phenotype dubbed therapy-induced senescence (TIS). High cellular heterogeneity in samples including TIS cells can impede confident determination of senescence-specific factors, frustrating discovery of markers and targets for functional analysis. As a TIS study model, we treated murine melanoma cells with the chemotherapeutic etoposide, applied a live-cell fluorescent SA-b-Gal senescence assay, and utilized fluorescence-activated cell sorting (FACS) to enrich TIS cells. Enriched senescent cell samples were subjected to mass spectrometry and label-free quantitative proteomics analysis, alongside proliferating and quiescent cell samples. Systems biology analysis revealed that senescent cells overexpress proteins and pathways regulating glycolipid processing, lipid metabolism, and lipid peroxidation. Senescence-associated activation of numerous glycosidases was observed, along with elevated cell surface expression of several major lipid regulatory proteins. Senescent cells were found to contain abundant lipid droplets and to import various types of extracellular lipids in correlation with extent of SA-b-Gal expression, and tumor cells were observed to spontaneously senesce in the presence of excess ceramide or triglycerides. Redox-induced lipid peroxidation, resulting in accumulation of cellular reactive aldehydes and consequent expression of aldehyde detoxification enzymes, was observed to be a key feature of TIS induced by three DNA-damaging chemotherapeutics.

2017-11-06 | PXD006216 | Pride

Expression data comparing Normal Human Bronchial Epithelial Cells (NHBE) cells in states of senescence, proliferation and quiescence

Project description:EGFR inhibitor Erlotinib treatment can induce NHBE into profound cell cycle arrest that include senescence and quiescence. Because senescent cells feature high senescence assocaited-beta-galactosidase(SA-β-gal) activty, which has been used as marker for FACS based collection of senescent and quiescent cells, respectively.

2018-07-27 | GSE100014 | GEO

Wnt5A promotes an adaptive, senescent-like stress response, while continuing to drive invasion in melanoma cells.

Project description:We have previously shown that Wnt5A drives invasion in melanoma. We have also shown that Wnt5A promotes resistance to therapy designed to target the BRAF(V600E) mutation in melanoma. Here, we show that melanomas characterized by high levels of Wnt5A respond to therapeutic stress by increasing p21 and expressing classical markers of senescence, including positivity for senescence-associated β-galactosidase (SA-β-gal), senescence-associated heterochromatic foci (SAHF), H3K9Me chromatin marks, and PML bodies. We find that despite this, these cells retain their ability to migrate and invade. Further, despite the expression of classic markers of senescence such as SA-β-gal and SAHF, these Wnt5A-high cells are able to colonize the lungs in in vivo tail vein colony-forming assays. This clearly underscores the fact that these markers do not indicate true senescence in these cells, but instead an adaptive stress response that allows the cells to evade therapy and invade. Notably, silencing Wnt5A reduces expression of these markers and decreases invasiveness. The combined data point to Wnt5A as a master regulator of an adaptive stress response in melanoma, which may contribute to therapy resistance.

2015-08-07 | GSE50004 | GEO

Unveiling E2F4, TEAD1 and AP-1 as regulatory transcription factors of the replicative senescence program by multi-omics analysis

Project description:Senescence, a stable state of growth arrest, affects many physiological and pathophysiological processes, especially aging. Previous work has indicated that transcription factors (TFs) play a role in regulating senescence. However, a systematic study of regulatory TFs during replicative senescence (RS) using multi-omics analysis is still lacking. Here, we generated time-resolved RNA-seq, reduced representation bisulfite sequencing (RRBS) and ATAC-seq datasets during RS of mouse skin fibroblasts, which demonstrated that an enhanced inflammatory response and reduced proliferative capacity were the main characteristics of RS in both the transcriptome and epigenome. Through integrative analysis and genetic manipulation, we found that transcription factors E2F4, TEAD1 and AP-1 are key regulators of RS. Overexpression of E2f4 improved cellular proliferative capacity, attenuated SA-β-Gal activity and changed RS-associated differentially methylated sites (DMSs). Moreover, knockdown of Tead1 attenuated SA-β-Gal activity and partially altered the RS-associated transcriptome. In addition, knockdown of Atf3, one member of AP-1 superfamily TFs, reduced Cdkn2a (P16) expression in pre-senescent fibroblasts. Taken together, results of this study identified transcription factors regulating the senescence program through multi-omics analysis, providing potential therapeutic targets for anti-aging.

2021-10-01 | GSE179880 | GEO

Unveiling E2F4, TEAD1 and AP-1 as regulatory transcription factors of the replicative senescence program by multiomics analysis

2021-10-08 | GSE185416 | GEO

Muscle injury induces a transient senescence-like state that is required for myofiber growth during muscle regeneration

Project description:Cellular senescence is the irreversible arrest of normally dividing cells and is driven by the cell cycle inhibitors Cdkn2a, Cdkn1a, and Trp53. Senescent cells are implicated in chronic diseases and tissue repair through their increased secretion of proinflammatory factors known as the senescence-associated secretory phenotype (SASP). Here, we use spatial transcriptomics and single-cell RNA sequencing (scRNAseq) to demonstrate that cells displaying senescent characteristics are “transiently" present within regenerating skeletal muscle and within the muscles of D2-mdx mice, a model of Muscular Dystrophy. Following injury, multiple cell types including macrophages and fibro-adipogenic progenitors (FAPs) upregulate senescent features such as senescence pathway genes, SASP factors, and senescence-associated beta-gal (SA-β-gal) activity. Importantly, when these cells were removed with ABT-263, a senolytic compound, satellite cells are reduced, and muscle fibers were impaired in growth and myonuclear accretion.

2022-10-11 | GSE214892 | GEO

PUVA pretreatment leads to significant reduction in imiquimod induced psoriatic phenotype with gene expression signature associated with senescence

Project description:PUVA pretreatment leads to develop early senescence confirmed by p16, p21 and SA-β-GAL positivity which was completely normalised by longer gap. Indicating that PUVA pretreatment causes conditioning set of genes that led to a marked delay in psoriasis development.

2018-01-01 | GSE100774 | GEO

Shp2 Signaling Suppresses Senescence in PyMT-induced Mammary Gland Cancer in Mice [Mouse430_2 array]

Project description:In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated β-gal (SA-β-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, Focal adhesion kinase and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies which rely on senescence induction by inhibiting Shp2 or controlling its target gene products may be useful in blocking breast cancer.

2015-03-06 | GSE50517 | GEO

Shp2 Signaling Suppresses Senescence in PyMT-induced Mammary Gland Cancer in Mice [Mouse430A_2 array]

2015-03-06 | GSE50516 | GEO

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