Reprogramming the Methylome: Erasing Memory and Creating Diversity

The inheritance of epigenetic marks, in particular DNA methylation, provides a molecular memory that ensures faithful commitment to transcriptional programs during mammalian development. Epigenetic reprogramming results in global hypomethylation of the genome together with a profound loss of memory, which underlies naive pluripotency. Such global reprogramming occurs in primordial germ cells, early embryos, and embryonic stem cells where reciprocal molecular links connect the methylation machinery to pluripotency. Priming for differentiation is initiated upon exit from pluripotency, and we propose that epigenetic mechanisms create diversity of transcriptional states, which help with symmetry breaking during cell fate decisions and lineage commitment. This Perspective discusses synergistic mechanisms that result in epigenetic memory loss in PGCs, the early embryo, and naive ESCs. Links between pluripotency and loss of epigenetic memory and connections between heterogeneous DNA methylation and lineage priming are also explored.