Pathway Profiling of Replicative and Induced Senescence
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE60340 | GEO | 2015/02/01
SECONDARY ACCESSION(S): PRJNA258058
REPOSITORIES: GEO
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Project description:RNA-seq was performed on LFS MDAH041 cells that were young (PD10-12), aging (PD17-19) and replicatively senescent (PD28-30), as well as spontaneously immortal cells and cells that were induced into senescence or quiescence, in order to profile the pathways common in all 4 types of sensecence and the pathways affected as a cell approaches senescence. RNA was sequenced in biological triplicates of each sample using the Illumina HiSeq2000
2015-02-01 | E-GEOD-60340 | biostudies-arrayexpress
Project description:Cellular senescence is classified into two groups; replicative and premature senescence. The gene expression and epigenetic changes differ between two groups of senescence, replicative and premature senescence, and cell types. Normal human diploid fibroblast TIG-3 cells have often been used in cellular senescence research, however, their epigenetic profiles are not fully understood. To elucidate how cellular senescence is epigenetically regulated in TIG-3 cells, we analyzed the gene expression and DNA methylation profiles of three types of senescent cells, namely, replicative senescent, ras-induced senescent (RIS), and non-permissive temperature-induced senescent SVts8 cells, using gene expression and methylation microarrays. The expression of genes involved in the cell cycle and immune response was commonly either down- or up-regulated in the three types of senescent cells, respectively. The sequential alteration of the DNA methylation level in a time-dependent manner was observed in replicatively senescent cells, but not in premature senescent cells. The integrated analysis of gene expression and methylation in replicatively senescent cells demonstrated that the expression of 759 genes involved in the cell cycle and immune response was associated with methylation. Furthermore, hypomethylation occurred in non-CpG island regions (open sea) of the genes exhibiting increased expression as well as non-CpG island promoters of the genes related to the immune response. Several miRNAs regulated through DNA methylation were found to affect the expression of their target genes. Taken together, these results indicate that DNA methylation contributes to the introduction and establishment of replicative senescence partly by regulating gene expression.
2017-02-12 | GSE90942 | GEO
Project description:The aim of the present study was to provide a comprehensive characterization of whole genome DNA methylation patterns in replicative and ionizing irradiation- or doxorubicin-induced premature senescence, exhaustively exploring epigenetic modifications in three different human cell types: in somatic diploid skin fibroblasts and in bone marrow- and adipose-derived mesenchymal stem cells. With CpG-wise differential analysis three epigenetic signatures were identified: a) cell type- and treatment-specific signature; b) cell type-specific senescence-related signature; and c) cell type-transversal replicative senescence-related signature. Cluster analysis revealed that only replicatively senescent cells created a distinct group reflecting notable alterations in the DNA methylation patterns accompanying this cellular state. Replicative senescence-associated epigenetic changes seemed to be of such an extent that they surpassed interpersonal dissimilarities. Enrichment in pathways linked to the nervous system and involved in the neurological functions was shown after pathway analysis of genes involved in the cell type-transversal replicative senescence-related signature. Although DNA methylation clock analysis provided no statistically significant evidence on epigenetic age acceleration related to senescence, a persistent trend of increased biological age in replicatively senescent cultures of all three cell types was observed. Overall, this work indicates the heterogeneity of senescent cells depending on the tissue of origin and the type of senescence inducer that could be putatively translated to a distinct impact on tissue homeostasis.
2023-03-20 | GSE227160 | GEO
Project description:We applied in parallel RNA-Seq and Ribosome-profiling analyses to immortalized human primary BJ fibroblast cells under the following conditions: normal proliferation, quiescence (induced by serum depletion), senescence (induced by activation of the oncogenic RASG12V gene, and examined at early (5 days; pre-senescent state) and late (14 days; fully senescent state) time points), and neoplastic transformation (induced by RASG12V in the background of stable p53 and p16INK4A knockdowns and SV40 small-T expression. RNA-seq, using Illumina HiSeq 2000, was applied to BJ cells under 5 conditions: proliferation, quiescence, pre-senescence, full-senescence, and transfomed. Ribosome profiling, using Illumina HiSeq 2000, was applied to BJ cells under 5 conditions: proliferation, quiescence, pre-senescence, full-senescence, and transfomed.
2013-03-24 | E-GEOD-42509 | biostudies-arrayexpress
Project description:<p><strong>BACKGROUND:</strong> Periodontal ligament mesenchymal stem cells (PDLSCs) are a promising cell resource for cell-based regenerative medicine in dentistry. PDLSCs inevitably acquire a senescent phenotype after prolonged in vitro expansion, and the key regulators of cells during replicative senescence remain unclear.</p><p><strong>METHODS:</strong> We cultured periodontal ligament stem cells to passages 4, 10 and 20 (P4, P10, P20). The senescent phenotypes, proliferation and migration ability of PDLSCs (P4, P10, P20) were detected, and non-targeted metabonomic sequencing was performed. We treated PDLSCs with AICAR and detected the expression of FOXO1, FOXO3a, FOXO6 and AMPK phosphorylation (p-AMPK) levels of replicating senescent PDLSCs to explore the correlation between the metabolic changes and the AMPK pathway.</p><p><strong>RESULTS:</strong> Immunofluorescence staining of γ-H2AX, β-galactosidase staining, cell scratch test and qPCR were performed to confirm the occurrence of replicative senescence in PDLSCs during passaging. Three groups of cells at passage 4 (P4), passage 10 (P10) and passage 20 (P20) were collected for non-targeted metabolomics analysis. Metabonomic sequencing showed that the metabolism of replicative senescence in PDLSCs varied significantly. In particular, the content of fatty acid metabolites decreased with senescence, including capric acid, stearic acid, myristic acid and dodecanoic acid. KEGG pathway analysis showed that the AMPK signaling pathway was closely related to AMP levels. The AMP:ATP ratio increased in senescent PDLSCs; however, the levels of p-AMPK and the profile of FOXO1 and FOXO3a, which are downstream of the AMPK signaling pathway, decreased with senescence. We treated PDLSCs with AICAR, an activator of the AMPK pathway, and the phosphorylated AMPK level at P20 PDLSCs was partially restored. </p><p><strong>CONCLUSION:</strong> In summary, our study suggests that the metabolic process of PDLSCs is active in the early stage of senescence, prefers to consume fatty acids, and is attenuated in the later stages of senescence. AMP accumulates in replicative senescent PDLSCs; however, the sensitivity of AMPK phosphorylation sites is impaired, causing senescent PDLSCs to fail to respond to changes in energy metabolism. Our findings provide a new basis for the clinical application of periodontal ligament stem cells.</p>
2022-11-15 | MTBLS4568 | MetaboLights
Project description:There is a paradigm that cancer cells are immortal, which indicates that they have an ability to bypass cellular senescence. This is often linked with an expression of telomerase which restores the telomeric DNA. Cellular senescence may be induced in cancer cells by their exposure to clinically relevant doses of ionizing radiation (radiotherapy) and chemotherapy. It means that even though cancer cells avoided senescence in the course of their immortalization, they preserved intact molecular effectory pathways leading to senescence under some therapy-related conditions. Interestingly, it has repeatedly been described that tumors from patients who had no received any form of therapy also contain a fraction of cells bearing morphological and biochemical signature of senescence. Taking this into account, the goal of our project was to examine the presence of spontaneously senescent ovarian cancer cells in vivo and in vitro, and to describe molecular mechanisms underlying this phenomenon.
2019-05-24 | GSE131715 | GEO
Project description:Cellular senescence is a tumor suppressor mechanism, and immortalization facilitates neoplastic transformation. Both mechanisms may be highly relevant to hepatocellular carcinoma (HCC) development and its molecular heterogeneity. Cellular senescence appears to play a major role in liver diseases. Chronic liver diseases are associated with progressive telomere shortening leading senescence that is observed highly in cirrhosis, but also in some HCC. We previously described the generation of immortal and senescence-programmed clones from HCC-derived Huh7 cell line. We used microarrays to detail the global programme of gene expression profiles of immortal and senescent-programmed clones.
2013-05-23 | GSE17546 | GEO
Project description:Cellular senescence is a program of irreversible cell cycle arrest that normal cells undergo in response to progressive shortening of telomeres, changes in telomeric structure, oncogene activation or oxidative stress. The underlying signalling pathways, potentially of major clinicopathological relevance, are unknown. A major stumbling block to studying senescence has been the absence of suitable model systems because of the asynchrony of this process in heterogeneous cell populations. To simplify this process many investigators study oncogene-induced senescence due to expression of activated oncogenes where senescence occurs prematurely without telomere attrition and can be induced acutely in a variety of cell types. We have taken a different approach by making use of the finding that reconstitution of telomerase activity by introduction of the catalytic subunit of human telomerase alone is incapable of immortalising all human somatic cells, but inactivation of the p16-pRB and p53-p21 pathways are required in addition. The ability of SV40 large T antigen to inactivate the p16-pRB and p53-p21 pathways has enabled us to use a thermolabile mutant of LT antigen, in conjunction with hTERT, to develop conditionally immortalised human (HMF3A) fibroblasts that are immortal but undergo an irreversible growth arrest when the thermolabile LT antigen is inactivated leading to activation of pRB and p53. When these cells cease dividing, senescence-associated- b-galactosidase activity is induced and the growth-arrested cells have morphological features and express genes in common with senescent cells. Since these cells growth arrest in a synchronous manner they are an excellent starting point for dissecting the pathways that underlie cellular senescence and act downstream of p16-pRB and p53-p21 pathways. We have combined genome-wide expression profiling with genetic complementation to undertake identification of genes that are differentially expressed when these conditionally immortalised human fibroblasts undergo senescence upon activation of the p16-pRB and p53-p21 tumour suppressor pathways. Genes differentially expressed upon senescence will be identified by comparing arrays from growing versus senescent cells. Changes in gene expression due to the temperature shift will be eliminated by comparing with array data from the non-conditional HMF3S cells grown at 34°C ±0.5°C and 38°C ±0.5°C. To determine if the changes in gene expression upon senescence are specific and reversible, the set of differential genes will then be overlaid with array data from cells in which senescence has been bypassed by inactivation of the p16-pRB and p53-p21 tumour suppressor pathways
2011-01-21 | E-GEOD-24810 | biostudies-arrayexpress
Project description:Cellular senescence is a dynamic tumor suppression mechanism that limits the proliferation of impaired cells, by executing a stable cell cycle arrest. Understanding the molecular pathways and regulatory circuits that are involved in the process of senescence is presently incomplete. In this study, we determined the changes in gene expression during the establishment of replicative senescence, by comparing the expression profiles of young and senescent human umbilical vein endothelial cells (HUVECs). Exploration of array data using ingenuity pathway analysis showed that genes involved in cell cycle regulation, cellular assembly and organization, DNA replication, recombination and repair were significantly down regulated during senescence.
2022-01-27 | GSE195517 | GEO
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