Locally-correlated kinetics of post-replication DNA methylation reveals processivity and region-specificity in DNA methylation maintenance

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 maintenance 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 postreplication in cells. We find that DNA methylation maintenance rates on individual CpGs are locally correlated, and the degree of this correlation varies by genomic regional context. Applying theory of one-dimensional diffusion of proteins along DNA, we show that exponential decay of methylation rate correlation with genomic distance is consistent with enzyme processivity. Our results provide quantitative evidence of genome-wide methyltransferase processivity in vivo. From the experiment-derived correlations, we estimate that an individual methyl-transferase methylates neighbor CpGs in sequence if they are 36 basepairs apart, on average. But other mechanisms of coupling dominate for inter-CpG distances past ~ 100 basepairs. Our study demonstrates that quantitative insights into enzymatic mechanisms can be obtained from replication-associated, cell-based genome-wide measurements, by combining data-driven statistical analyses with hypothesis-driven mathematical modeling.