Naive pluripotency is associated with global DNA hypomethylation

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Abstract
Naive pluripotent embryonic stem cells (ESCs) and embryonic germ cells (EGCs) have distinct developmental origins. Genome-wide expression and global DNA-methylation analyses now reveal that ESCs and ESGs are highly similar at the transcriptome level and, contrary to previous assumptions, are both characterized by DNA hypomethylation. Also, global methylation levels in both ESCs and EGCs are directly responsive to culture conditions. Naive pluripotent embryonic stem cells (ESCs) and embryonic germ cells (EGCs) are derived from the preimplantation epiblast and primordial germ cells (PGCs), respectively. We investigated whether differences exist between ESCs and EGCs, in view of their distinct developmental origins. PGCs are programmed to undergo global DNA demethylation; however, we find that EGCs and ESCs exhibit equivalent global DNA methylation levels. Inhibition of MEK and Gsk3b by 2i conditions leads to pronounced reduction in DNA methylation in both cell types. This is driven by Prdm14 and is associated with downregulation of Dnmt3a and Dnmt3b. However, genomic imprints are maintained in 2i, and we report derivation of EGCs with intact genomic imprints. Collectively, our findings establish that culture in 2i instills a naive pluripotent state with a distinctive epigenetic configuration that parallels molecular features observed in both the preimplantation epiblast and nascent PGCs.