Mouse embryonic stem cells (ESCs) and embryonic germ cells (EGCs) are both pluripotent cell types derived from distinct developmental stages. Despite sharing many characteristics, some differences have been reported between the two cell types. For instance, EGCs generally lack of DNA methylation at imprinted regions and they have been suggested to display overall global hypomethylation. These characteristics have always been regarded as reflective of their derivation origin from primordial germ cells (PGCs), whereas ESCs are derived from preimplantation blastocysts. A large set of newly derived, genetically matched ESC and EGC lines has enabled us to clarify several of these observations at genome-wide scale. DNA methylation analysis of ESCs and EGCs, in particular lines derived from both sexes demonstrates that the DNA methylation profiles of female ESCs and EGCs are comparable low, while the male cell lines all share a more hypermethylated genome. The observed hypomethylation is not restricted to promoters but is also evident in many retroelements including the regions often regarded as resistant to demethylation. Mechanistically it appears that the two active X chromosomes in female cells are involved. Specifically, we find that the X-linked gene Dusp9 may play a central role in the regulation of DNA methylation via the inhibition of Erk signaling. Taken together, our results provide novel mechanistic insights as well as clarify that it is not the EGC identity that caused the global hypomethylation in prior studies, but rather the fact that the lines in those experiments happened to be female EGCs
