Genome-scale oscillations in DNA methylation during exit from pluripotency

Summary Pluripotency is accompanied by the erasure of parental epigenetic memory with naïve pluripotent cells exhibiting global DNA hypomethylation both in vitro and in vivo . Exit from pluripotency and priming for differentiation into somatic lineages is associated with genome-wide de novo DNA methylation. We show that during this phase, coexpression of enzymes required for DNA methylation turnover, DNMT3s and TETs, promotes cell-to-cell variability in this epigenetic mark. Using a combination of single-cell sequencing and quantitative biophysical modelling, we show that this variability is associated with coherent, genome-scale, oscillations in DNA methylation with an amplitude dependent on CpG density. Analysis of parallel single-cell transcriptional and epigenetic profiling provides evidence for oscillatory dynamics both in vitro and in vivo . These observations provide fresh insights into the emergence of epigenetic heterogeneity during early embryo development, indicating that dynamic changes in DNA methylation might influence early cell fate decisions. Highlights Co-expression of DNMT3s and TETs drive genome-scale oscillations of DNA methylation Oscillation amplitude is greatest at a CpG density characteristic of enhancers Cell synchronisation reveals oscillation period and link with primary transcripts Multiomic single-cell profiling provides evidence for oscillatory dynamics in vivo