Abstract
DNA methylation occurs predominantly on cytosine-phosphate-guanine (CpG) dinucleotides in the mammalian genome, and the methylation landscape is maintained over mitotic cell division. It has been posited that coupling of methylation activity among neighboring CpGs is critical to collective stability over cellular generations, however the mechanism of this coupling is unclear. We used mathematical models and stochastic simulation to analyze data from experiments that probe genome-wide methylation of nascent DNA post-replication. We find that DNA methylation maintenance shows genomic-region-specific kinetics, indicating influence of local CpG density and chromatin accessibility on methyltransferase activity and inter-CpG coupling. We uncover evidence of processive methylation kinetics in post-replication DNA, which manifests as exponential decay of methylation rate correlation on neighboring CpGs. Our results indicate that processivity is a component of inter-CpG-coupling that occurs globally throughout the genome, but other mechanisms of coupling dominate for inter-CpG distances past 100 basepairs. By decomposing local methylation correlations into processive and non-processive components, we estimate that an individual methyltransferase methylates neighbor CpGs in sequence if they are 36 basepairs apart, on average. Our study demonstrates that detailed information on epigenomic dynamics can be gleaned from replication-associated, cell-based genome-wide measurements, by combining data-driven statistical analyses with hypothesis-driven mathematical modeling.
Competing Interest Statement
The authors have declared no competing interest.
