Chemical modification of DNA by methylation of cytosine (5meC) at CpG sequences is thought to provide a stable and heritable mark that allows early developmental signals to produce long-lasting alternative gene expression states. Unfortunately, the epigenetics field has been largely contented for almost three decades with a simple model for inheritance of DNA methylation, where a maintenance methylase acts on individual hemimethylated CpGs to faithfully restore methylation. We argue that it is time for a paradigm shift in thinking about inheritance of DNA methylation.
Our systematic theoretical analysis, simulating CpG islands through many cell divisions under many possible reaction schemes, shows that the ‘standard model’ is inconsistent with experimental observations, producing methylation patterns that steadily degrade over time. In contrast, true stability of both high-methylation states and low-methylation states of CpG islands can be achieved if methylation and demethylation rates at each CpG are affected by the methylation status of nearby CpGs, that is, if CpGs collaborate. Collaboration can be provided by simple recruitment of methylation/demethylation enyzmes by methylated/unmethylated CpGs in a positive feedback reaction. Testing over 100,000,000 reaction schemes, we show that such dynamic collaborative systems can provide highly stable and heritable states, both hypermethylated and hypomethylated, of a CpG island.
In the standard model, active demethylation works against stable methylation inheritance. In collaborative systems, demethylation can be an important contributor to inheritance. In particular, collaborative demethylation strengthens inheritance and can also provide a mechanism for achieving the spatial distribution of methylation in chromosomes, where high-density CpG islands can be stably and heritably hypomethylated or hypermethylated while the surrounding low-density ‘sea’ remains constantly hypermethylated. We thus predict that demethylation enzymes will be recruited by unmethylated CpGs.