Molecular 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.
Bibliographical noteFunding Information:
The authors thank Uri Ben-david, Yonatan Stelzer, Daniel Ronen, Tomer Halevy, and Uri Weissbein for critically reading this manuscript and Tamar Golan-Lev for her assistance with the graphical design of the figures. We thank Yonatan Stelzer for his assistance with this work. N.B. is the Herbert Cohn Chair in Cancer Research. This research was partially supported by the Legacy Heritage Biomedical Science Partnership Program of the Israel Science Foundation (grant 269/12) and the Juvenile Diabetes Research Foundation (grant 1-2011-555). The research leading to these results has also received partial funding from the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115439 (StemBANCC), resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. This publication reflects only the author’s views and neither the IMI JU nor EFPIA nor the European Commission are liable for any use that may be made of the information contained therein. For more information, go to http://www.stembancc.org/ .