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Potential roles of DNA methylation in the initiation and establishment of replicative senescence revealed by array-based methylome and transcriptome analyses

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE90942 | GEO | 2017/02/12

SECONDARY ACCESSION(S): PRJNA356427

REPOSITORIES: GEO

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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.

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Potential roles of DNA methylation in the initiation and establishment of replicative senescence revealed by array-based methylome and transcriptome analyses

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