Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Genome-wide methylation maps for Proliferating and Senescent cells

ABSTRACT: Altered DNA methylation and associated destabilization of genome integrity and function is a hallmark of cancer. Replicative senescence imposes a limit on proliferative potential that all cancer cells must bypass. Compared to proliferating cells, senescent cells exhibit marked chromatin re-organization. Here we show by whole-genome single-nucleotide bisulfite sequencing that replicative senescent human cells exhibit widespread alterations in their DNA methylome. These changes are linked to mislocalization of the maintenance DNA methyltransferase (DNMT1) in cells approaching senescence, altered replication-coupled DNA methylation and de-repression of repetitive satellite sequences. Deficiency of DNMT1 triggers chromatin changes characteristic of senescence and expression of satellite sequences. Most importantly, but paradoxically, gains and losses of methylation in replicative senescence are similar to those in cancer, and this M-bM-^@M-^XreprogrammedM-bM-^@M-^Y methylation landscape is largely retained when cells escape or bypass senescence. In sum, altered regulation of DNMT1 in cells approaching replicative senescence contributes to changes in chromatin structure and function. Consequently, if senescent cells escape the proliferative barrier, they already harbor epigenetic changes likely to promote malignancy. Examination of methylation status in IMR90 cells

ORGANISM(S): Homo sapiens

SUBMITTER: Tony McBryan

PROVIDER: E-GEOD-48580 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Senescent cells harbour features of the cancer epigenome.

Cruickshanks Hazel A HA McBryan Tony T Nelson David M DM Vanderkraats Nathan D ND Shah Parisha P PP van Tuyn John J Singh Rai Taranjit T Brock Claire C Donahue Greg G Dunican Donncha S DS Drotar Mark E ME Meehan Richard R RR Edwards John R JR Berger Shelley L SL Adams Peter D PD

Nature cell biology 20131124 12

Altered DNA methylation and associated destabilization of genome integrity and function is a hallmark of cancer. Replicative senescence is a tumour suppressor process that imposes a limit on the proliferative potential of normal cells that all cancer cells must bypass. Here we show by whole-genome single-nucleotide bisulfite sequencing that replicative senescent human cells exhibit widespread DNA hypomethylation and focal hypermethylation. Hypomethylation occurs preferentially at gene-poor, late ...[more]

PMID: 24270890

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Project description:BACKGROUND: 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.METHODS: 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.RESULTS: 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. CONCLUSION: 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.

Dataset Information

Genome-wide methylation maps for Proliferating and Senescent cells

Publications

Senescent cells harbour features of the cancer epigenome.

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