Antagonistic histone post-translational modifications improve the fidelity of epigenetic inheritance - a Bayesian perspective

Abstract

Histone Post-Translational Modifications (PTMs) are important epigenetic marks regulating gene expression. The specific pattern of histone PTMs present over the gene is critical for turning on/off the expression of the correspond ing gene. During DNA replication in mitotic cells, the histone PTMs are dislodged from the mother chromatid, ahead of the replication fork, and distributed uniformly at random among the daughter chromatids. Building on our previous work which modelled the inheritance of a single PTM, the current work considers the effect of an additional antagonistic PTM. We model the joint PTM sequence by an appropriate Markov model and the DNA replication fork as a noisy communication channel. The optimal Bayesian sequence estimator is then employed at each of the daughter chromatids to reconstruct the mother PTM pattern. A high-fidelity reconstruction, aided by the enzyme machinery, is shown to be possible in the presence of epigenetic memory. The structural properties derived for the optimal estimator are then verified through simulations, which show the improvement in fidelity of inheritance in the presence of antagonism. This is further validated through recent experimental data.