DNA methylation heterogeneity induced by collaborations between enhancers.

During mammalian embryo development, reprogramming of DNA methylation plays important roles in the erasure of parental epigenetic memory and the establishment of na\"{i}ve pluripogent cells. Multiple enzymes that regulate the processes of methylation and demethylation work together to shape the pattern of genome-scale DNA methylation and guid the process of cell differentiation. Recent availability of methylome information from single-cell whole genome bisulfite sequencing (scBS-seq) provides an opportunity to study DNA methylation dynamics in the whole genome in individual cells, which reveal the heterogeneous methylation distributions of enhancers in embryo stem cells (ESCs). In this study, we developed a computational model of enhancer methylation inheritance to study the dynamics of genome-scale DNA methylation reprogramming during exit from pluripotency. The model enables us to track genome-scale DNA methylation reprogramming at single-cell level during the embryo development process, and reproduce the DNA methylation heterogeneity reported by scBS-seq. Model simulations show that DNA methylation heterogeneity is an intrinsic property driven by cell division along the development process, and the collaboration between neighboring enhancers is required for heterogeneous methylation. Our study suggest that the mechanism of genome-scale oscillation proposed by Rulands et al. (2018) might not necessary to the DNA methylation during exit from pluripotency.