(A) Both ICM cells and PGCs are globally hypomethylated during development, regardless of sex. However, ESCs and EGCs, derived from explanted ICM and PGC cells, exhibit distinct DNA methylation status according to their sex. Female ESCs/EGCs maintain global hypomethylation, which is in part due to elevated expression of the X-linked Dusp9 gene. Upregulation of DUSP9 attenuates MAPK signaling and, directly or indirectly, leads to downregulation of DNMT3A/3B and UHRF1.
(B) Global DNA methylation levels in fusion hybrids between MEFs and either ESCs or EGCs are dictated by the ratio of active X chromosomes (XA) to autosomes (A) rather than the absolute number of XAs. (A–B) Red, global DNA hypomethylation; blue, global DNA hypermethylation.