期刊
STEM CELL REPORTS
卷 12, 期 5, 页码 1113-1128出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2019.04.008
关键词
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资金
- cancer research grant P-CREATE, Japan Agency for Medical Research and Development (AMED)
- Japan Agency for Medical Research and Development (AMED)
- SICORP, AMED
- JSPS KAKENHI [18H04026, 15J05792]
- Takeda Science Foundation
- Naito Foundation
- AMED-CREST [JP18gm1110004, JP18gm0610017]
- Core Center for iPS Cell Research, Research Center Network for Realization of Regenerative Medicine, AMED
- iPS Cell Research Fund
- World Premier International Research Center Initiative, MEXT, Japan
- Grants-in-Aid for Scientific Research [18H04026, 15J05792] Funding Source: KAKEN
CpG islands (CGIs) including those at imprinting control regions (ICRs) are protected from de novo methylation in somatic cells. However, many cancers often exhibit CGI hypermethylation, implying that the machinery is impaired in cancer cells. Here, we conducted a comprehensive analysis of CGI methylation during somatic cell reprogramming. Although most CGIs remain hypomethylated, a small subset of CGIs, particularly at several ICRs, was often de novo methylated in reprogrammed pluripotent stem cells (PSCs). Such de novo ICR methylation was linked with the silencing of reprogramming factors, which occurs at a late stage of reprogramming. The ICR-preferred CGI hypermethylation was similarly observed in human PSCs. Mechanistically, ablation of Dnmt3a prevented PSCs from de novo ICR methylation. Notably, the ICR-preferred CGI hypermethylation was observed in pediatric cancers, while adult cancers exhibit genome-wide CGI hypermethylation. These results may have important implications in the pathogenesis of pediatric cancers and the application of PSCs.
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