Potential roles of DNA methylation in the initiation and establishment of replicative senescence revealed by array-based methylome and transcriptome analyses.
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.
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan.|Department of Biomolecular Science, Graduate School of Science, Toho University, Funabashi, Chiba, Japan.
Mizuho
M
Sakaki
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan.
Yukiko
Y
Ebihara
Department of Systems BioMedicine, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan.
Kohji
K
Okamura
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan.
Kazuhiko
K
Nakabayashi
Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan.
Arisa
A
Igarashi
Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan.
Kenji
K
Matsumoto
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan.
Kenichiro
K
Hata
Department of Biomolecular Science, Graduate School of Science, Toho University, Funabashi, Chiba, Japan.
Yoshiro
Y
Kobayashi
Department of Nutrition, Graduate School of Health Science, Kio University, Kitakatsuragi, Nara, Japan.
Kayoko
http://orcid.org/0000-0001-5573-7673
K
Maehara
D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D063990:Gene Ontology; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics