Abstract
Cellular senescence is classified into two groups: replicative and premature senescence. Gene expression and epigenetic changes are reported to differ between these two groups and cell types. Normal human diploid fibroblast TIG-3 cells have often been used in cellular senescence research; however, their epigenetic profiles are still 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, replicatively senescent, ras-induced senescent (RIS), and non-permissive temperature-induced senescent SVts8 cells, using gene expression and DNA 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 altered DNA methylation patterns were observed in replicatively senescent cells, but not in prematurely senescent cells. Interestingly, hypomethylated CpG sites detected on non-CpG island regions (“open sea”) were enriched in immune response-related genes that had non-CpG island promoters. The integrated analysis of gene expression and methylation in replicatively senescent cells demonstrated that differentially expressed 867 genes, including cell cycle- and immune response-related genes, were associated with DNA methylation changes in CpG sites close to the transcription start sites (TSSs). Furthermore, several miRNAs regulated in part through DNA methylation were found to affect the expression of their targeted genes. Taken together, these results indicate that the epigenetic changes of DNA methylation regulate the expression of a certain portion of genes and partly contribute to the introduction and establishment of replicative senescence.
Highlights
Cellular senescence is the irreversible cessation of cell proliferation [1] and is classified into two groups: replicative senescence and premature senescence [2]
To test the hypothesis that the differences in genetically identical cells are driven by different cellular responses to senescence, we examined array-based gene expression and DNA methylation profiles using genetically identical TIG-3 cells which had been induced to a senescent state by three different methods, namely, replicatively senescent, ras-induced senescent (RIS), and senescent SVts8 cells
A heatmap showed different patterns of gene expression among the three types of senescent cells, even though sample clustering indicated that replicatively senescent cells and RIS cells were closer than senescent SVts8 cells (Fig 2)
Summary
Cellular senescence is the irreversible cessation of cell proliferation [1] and is classified into two groups: replicative senescence and premature senescence [2]. Replicative senescence is caused by telomere shortening due to repeated DNA replication [3], while premature senescence is caused by stress, such as oncogene activation [4] and reactive oxygen species (ROS) [5], without apparent loss of telomere length and function. Cellular senescence has been shown to be associated with tumor suppression in several cancers [2, 6, 7], it has been reportedly involved in cancer progression through the induction of epithelial-mesenchymal transitions and tumor invasion [8]. Senescent cells secrete several factors associated with inflammation such as interleukin (IL)-6 and IL-8 [9], which are referred to as senescence-associated secretory phenotypes (SASP). Elucidation of the mechanism contributing to induction and establishment of the senescent state will help overcome such agerelated diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
