Collective oscillations of DNA methylation during exit from pluripotency

Pluripotency is associated with the erasure of parental epigenetic memory with naïve pluripotent cells exhibiting global DNA hypomethylation both in vitro and in vivo. Symmetry breaking in the early embryo and priming for differentiation into somatic lineages is accompanied by genome-wide de novo DNA methylation. During this phase, we find that the paradoxical co-expression of enzymes that promote methylation and demethylation, DNMT3s and TETs, promotes cell-to-cell variability in DNA methylation. We use a combination of novel single-cell sequencing techniques and methods from statistical physics, such as renormalization, to show that these factors drive coherent, genome-scale oscillations of DNA methylation. Analysis of parallel single-cell transcriptional and epigenetic profiling provides evidence for the same oscillatory dynamics in the living mouse embryo. These observations provide fresh insights into the emergence of collective epigenetic dynamics during early embryo development, suggesting that dynamic changes in DNA methylation may assist in regulating early fate decisions.