A quantitative model of MET1-catalyzed establishment and epigenetic inheritance of DNA methylation

Methylation of CG dinucleotides (mCG), which regulates genome function in eukaryotes, is epigenetically propagated by Dnmt1/MET1 methyltransferases via a semiconservative mechanism. How these enzymes accomplish stable epigenetic inheritance despite imperfect fidelity remains mysterious. Here we show that MET1 de novo activity, which is enhanced by existing proximate methylation, seeds and stabilizes mCG in Arabidopsis thaliana genes. MET1 activity is delimited by active DNA demethylation and counterbalanced by histone variant H2A.Z, natural variation in which accounts for high genic methylation in accessions from northern Sweden. Based on these observations, we develop a mathematical model that precisely recapitulates mCG inheritance dynamics and successfully predicts steady-state intragenic mCG patterns and their population-scale variation given only CG site spacing as input. Our results demonstrate how methylation patterns are created in plant genes, reconcile imperfect mCG maintenance with long-term stability, and establish a quantitative model for the epigenetic inheritance of mCG. Overall design: Bisulfite sequencing was carried out on leaf genomic DNA from a multi-generational Col-0 Arabidopsis thaliana lineage in different mutant genotypes