DNA methylation analysis of cellular senescence
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PROVIDER: PRJNA943492 | ENA |
REPOSITORIES: ENA
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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:Replicative senescent cells reportedly share similar DNA methylation changes with cancer cells, which are purported to facilitate tumorigenesis in cells bypassing senescence. However, we now report biologically critical and distinct patterns of DNA methylation evolution between replicative and oncogene-induced senescence and transformation in a classic human cell transformation model. While overall DNA methylation losses and gains occur in both replicative senescent and transformed cells, the patterns evolve more programmatically for the former and stochastically for the latter. Oncogene-induced senescence is an acute process involving minimal changes to DNA methylation. The stochastic DNA methylation alterations in transformation mainly involve a set of pro-survival promoter CpG-island methylation events targeting genes controlling development and differentiation processes, while the senescence-specific promoter changes occur in genes involved in positive regulation of cellular biosynthesis and macromolecular metabolism. The above set of pro-survival promoter CpG-island hypermethylation events, but not the senescence-specific events, are prone to occur in primary tumors and aging tissues. Importantly, cells manifest senescence-specific epigenomic patterns very early during commitment to senescence, and while these “near-senescent” cells can be immortalized, they are refractory to transformation by H-Ras oncoprotein (H-rasV12). The senescence-specific methylation is retained during immortalization and transformation attempts, suggesting it does not function to promote tumorigenesis. Thus, abnormalities in cancer-related methylation has their origins in aging and not replicative senescence, and senescence-associated methylation potentially prevents malignant transformation.
2018-01-31 | GSE91069 | GEO
Project description:Aberrant DNA methylation patterns are a hallmark of human cancers, prompting targeting of DNA methylation machinery to be explored as an anti-tumor strategy. DNA methyltransferase 1 (DNMT1) and ubiquitin like With PHD and Ring finger domains 1 (UHRF1) are crucial enzymes for DNA methylation maintenance. Unlike DNMT1, UHRF1 is overexpressed in most cancers and is a proven oncogene in vivo. Our previous work revealed that the degree of DNA methylation loss induced by UHRF1 depletion is more severe than DNMT1 depletion in colorectal cancer cells, indicating that targeting UHRF1 may be a more effective approach. Using an advanced chemical/genetic system, the auxin-inducible degron (AID) technology, we monitored the long-term effects of removing UHRF1 and/or DNMT1 in cancer cells, deciphering the mechanistic basis through bioinformatic tools. We found that chronic DNA demethylation triggers cancer cells to undergo cellular senescence. The loss of UHRF1 results in a more rapid and profound senescence phenotype than DNMT1 loss. Intriguingly, this senescence is not accompanied by DNA damage and functions independently of canonical senescence pathways such as p53 and p16/pRB. Non-canonical pathway investigations revealed that cytosolic p21 accumulation contributes to antiapoptosis during senescence. The suppression of cyclic GMP-AMP synthase (cGAS) also alleviates the senescence-associated secretory phenotype (SASP) and lysosomal activity, and this process is independent of stimulator of interferon genes (STING). Finally, xenograft experiments verified our findings in vivo. Our results highlight how DNA methylation protects cancer cells from non-canonical senescence and demonstrate the potential of targeting UHRF1 as a novel avenue for anticancer treatments.
2025-05-19 | GSE278103 | GEO
Project description:Aberrant DNA methylation patterns are a hallmark of human cancers, prompting targeting of DNA methylation machinery to be explored as an anti-tumor strategy. DNA methyltransferase 1 (DNMT1) and ubiquitin like With PHD and Ring finger domains 1 (UHRF1) are crucial enzymes for DNA methylation maintenance. Unlike DNMT1, UHRF1 is overexpressed in most cancers and is a proven oncogene in vivo. Our previous work revealed that the degree of DNA methylation loss induced by UHRF1 depletion is more severe than DNMT1 depletion in colorectal cancer cells, indicating that targeting UHRF1 may be a more effective approach. Using an advanced chemical/genetic system, the auxin-inducible degron (AID) technology, we monitored the long-term effects of removing UHRF1 and/or DNMT1 in cancer cells, deciphering the mechanistic basis through bioinformatic tools. We found that chronic DNA demethylation triggers cancer cells to undergo cellular senescence. The loss of UHRF1 results in a more rapid and profound senescence phenotype than DNMT1 loss. Intriguingly, this senescence is not accompanied by DNA damage and functions independently of canonical senescence pathways such as p53 and p16/pRB. Non-canonical pathway investigations revealed that cytosolic p21 accumulation contributes to antiapoptosis during senescence. The suppression of cyclic GMP-AMP synthase (cGAS) also alleviates the senescence-associated secretory phenotype (SASP) and lysosomal activity, and this process is independent of stimulator of interferon genes (STING). Finally, xenograft experiments verified our findings in vivo. Our results highlight how DNA methylation protects cancer cells from non-canonical senescence and demonstrate the potential of targeting UHRF1 as a novel avenue for anticancer treatments.
2025-05-19 | GSE278681 | GEO
Project description:Cellular senescence is classified into two types; replicative and premature senescence. Gene expression and epigenetic changes are different in types of senescence, replicative and premature senescence, and cell types. Normal human diploid fibroblast TIG-3 cells were often used in cellular senescence research, however, their epigenetic profiles were not fully understood. To elucidate how cellular senescence is epigenetically regulated in TIG-3 cells, we analyzed gene expression and DNA methylation profiles among 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 cell cycle and immune response were commonly either down- or up-regulated among three types of senescent cells, respectively. The sequential alteration of DNA methylation level was observed only in replicative senescent cells in a time-dependent manner, but not in premature senescent cells. The integrated analysis of gene expression and methylation in replicative senescent cells demonstrated that the expression of 759 genes involved in cell cycle and immune response was associated with methylation. Furthermore, hypomethylation occurred at non-CpG island regions (open sea) on the genes with increased expression as well as non-CpG promoter of the genes related to immune response. Several miRNAs regulated by DNA methylation were found to affect the expression of their target genes. Taken together, these results indicate that DNA methylation contributes to introduction and establishment of replicative senescence partly by regulating gene expression.
2017-02-12 | GSE81788 | GEO
Project description:Cellular senescence is classified into two types; replicative and premature senescence. Gene expression and epigenetic changes are different in types of senescence, replicative and premature senescence, and cell types. Normal human diploid fibroblast TIG-3 cells were often used in cellular senescence research, however, their epigenetic profiles were not fully understood. To elucidate how cellular senescence is epigenetically regulated in TIG-3 cells, we analyzed gene expression and DNA methylation profiles among 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 cell cycle and immune response were commonly either down- or up-regulated among three types of senescent cells, respectively. The sequential alteration of DNA methylation level was observed only in replicative senescent cells in a time-dependent manner, but not in premature senescent cells. The integrated analysis of gene expression and methylation in replicative senescent cells demonstrated that the expression of 759 genes involved in cell cycle and immune response was associated with methylation. Furthermore, hypomethylation occurred at non-CpG island regions (open sea) on the genes with increased expression as well as non-CpG promoter of the genes related to immune response. Several miRNAs regulated by DNA methylation were found to affect the expression of their target genes. Taken together, these results indicate that DNA methylation contributes to introduction and establishment of replicative senescence partly by regulating gene expression.
2017-02-12 | GSE81797 | GEO
Project description:Replicative senescent cells reportedly share similar DNA methylation changes with cancer cells, which are purported to facilitate tumorigenesis in cells bypassing senescence. However, we now report biologically critical and distinct patterns of DNA methylation evolution between replicative and oncogene-induced senescence and transformation in a classic human cell transformation model. While overall DNA methylation losses and gains occur in both replicative senescent and transformed cells, the patterns evolve more programmatically for the former and stochastically for the latter. Oncogene-induced senescence is an acute process involving minimal changes to DNA methylation. The stochastic DNA methylation alterations in transformation mainly involve a set of pro-survival promoter CpG-island methylation events targeting genes controlling development and differentiation processes, while the senescence-specific promoter changes occur in genes involved in positive regulation of cellular biosynthesis and macromolecular metabolism. The above set of pro-survival promoter CpG-island hypermethylation events, but not the senescence-specific events, are prone to occur in primary tumors and aging tissues. Importantly, cells manifest senescence-specific epigenomic patterns very early during commitment to senescence, and while these “near-senescent” cells can be immortalized, they are refractory to transformation by H-Ras oncoprotein (H-rasV12). The senescence-specific methylation is retained during immortalization and transformation attempts, suggesting it does not function to promote tumorigenesis. Thus, abnormalities in cancer-related methylation has their origins in aging and not replicative senescence, and senescence-associated methylation potentially prevents malignant transformation.
2018-01-31 | GSE91070 | GEO
Project description:Pluripotent stem cells evade replicative senescence, whereas other primary cells lose their proliferation and differentiation potential after a limited number of cell divisions M-bM-^@M-^S and this is accompanied by specific senescence-associated DNA methylation (SA-DNAm) changes. Here, we investigate SA-DNAm changes in mesenchymal stromal cells (MSC) upon long-term culture, irradiation-induced senescence, immortalization and reprogramming into induced pluripotent stem cells (iPSC) using high density HumanMethylation450 BeadChips. SA-DNAm changes are highly reproducible and occur particularly in intergenic and non-promoter regions of developmental genes. We demonstrate that ionizing irradiation, although associated with a very similar senescence phenotype, does not affect SA-DNAm. Furthermore, overexpression of the catalytic subunit of the human telomerase (TERT) or conditional immortalization with a doxycycline-inducible system (TERT and SV40 TAg) result in telomere extension but do not influence SA-DNAm. In contrast, we demonstrate that reprogramming into iPSC prevented SA-DNAm changes. Our results indicate that replicative senescence is associated with an epigenetically controlled process which stalls cells in a particular differentiated state, whereas irradiation-induced senescence and immortalization are not causally related to this process. Absence of SA-DNAm in pluripotent cells may play a central role for their escape from cellular senescence. Samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip
2012-09-24 | E-GEOD-37066 | biostudies-arrayexpress
Project description:Cellular senescence is classified into two types; replicative and premature senescence. Gene expression and epigenetic changes are different in types of senescence, replicative and premature senescence, and cell types. Normal human diploid fibroblast TIG-3 cells were often used in cellular senescence research, however, their epigenetic profiles were not fully understood. To elucidate how cellular senescence is epigenetically regulated in TIG-3 cells, we analyzed gene expression and DNA methylation profiles among 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 cell cycle and immune response were commonly either down- or up-regulated among three types of senescent cells, respectively. The sequential alteration of DNA methylation level was observed only in replicative senescent cells in a time-dependent manner, but not in premature senescent cells. The integrated analysis of gene expression and methylation in replicative senescent cells demonstrated that the expression of 759 genes involved in cell cycle and immune response was associated with methylation. Furthermore, hypomethylation occurred at non-CpG island regions (open sea) on the genes with increased expression as well as non-CpG promoter of the genes related to immune response. Several miRNAs regulated by DNA methylation were found to affect the expression of their target genes. Taken together, these results indicate that DNA methylation contributes to introduction and establishment of replicative senescence partly by regulating gene expression.
2017-02-12 | GSE81786 | GEO
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