Unified establishment and epigenetic inheritance of DNA methylation through cooperative MET1 activity

Methylation of CG dinucleotides (mCG), which regulates eukaryotic genome functions, is epigenetically propagated by Dnmt1/MET1 methyltransferases. How mCG is established and transmitted across generations despite imperfect enzyme 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 restricted by active demethylation and suppressed by histone variant H2A.Z. Based on these observations, we develop a mathematical model that precisely recapitulates mCG inheritance dynamics and predicts intragenic mCG patterns and their population-scale variation given only CG site spacing as input. The model reveals that intragenic mCG undergoes large, millennia-long epigenetic fluctuations, and can therefore mediate evolution on this timescale. Our results demonstrate how genic methylation patterns are created, reconcile imperfect mCG maintenance with long-term stability, and establish a quantitative model that unifies the establishment and epigenetic inheritance of mCG.