De Novo DNA Methylation at Imprinted Loci during Reprogramming into Naive and Primed Pluripotency

Summary: 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. : In this article, Yamada, Yamamoto and colleagues show that Dnmt3a-mediated DNA methylation occurs at imprinting loci during reprogramming into naive and primed PSCs. Similar de novo ICR methylation is detected in pediatric cancers, which raises the possibility that reprogramming is involved in development of childhood cancers. Keywords: pluripotent stem cells, naive and primed pluripotency, reprogramming, pediatric cancers, DNA methylation, genomic imprinting, CpG islands, Dnmt3