Global Indiscriminate Methylation in Cell-Specific Gene Promoters following Reprogramming into Human Induced Pluripotent Stem Cells

• Gene expression and DNA methylation profiles were compared for various human iPSCs
• Reprogramming is accompanied by extensive DNA methylation in CpG-poor promoters
• Hypermethylation occurs in cell-specific genes regardless of expression status
• Methylation regulates silencing of CpG-poor promoters in a nonspecific manner

SummaryMolecular reprogramming of somatic cells into human induced pluripotent stem cells (iPSCs) is accompanied by extensive changes in gene expression patterns and epigenetic marks. To better understand the link between gene expression and DNA methylation, we have profiled human somatic cells from different embryonic cell types (endoderm, mesoderm, and parthenogenetic germ cells) and the iPSCs generated from them. We show that reprogramming is accompanied by extensive DNA methylation in CpG-poor promoters, sparing CpG-rich promoters. Intriguingly, methylation in CpG-poor promoters occurred not only in downregulated genes, but also in genes that are not expressed in the parental somatic cells or their respective iPSCs. These genes are predominantly tissue-specific genes of other cell types from different lineages. Our results suggest a role of DNA methylation in the silencing of the somatic cell identity by global nonspecific methylation of tissue-specific genes from all lineages, regardless of their expression in the parental somatic cells.