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

Histone Post-Translational Modifications (PTMs) are important epigenetic marks, whose specific pattern over the chromatin plays a critical role in turning the corresponding gene on/off. 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. We show that maintaining the fidelity of a primary PTM pattern, from the partial information available after replication, can be significantly improved by the presence of an additional antagonistic PTM sequence in the mother.

Building on our previous study which proposed mechanisms for maintaining fidelity by utilizing only half the parental nucleosomes, the current work considers the effect of an additional antagonistic PTM sequence. We represent the joint PTM sequence by an appropriate Markov model and the DNA replication fork as a noisy communication channel. An optimal Bayesian sequence estimator is then employed at each of the daughter chromatids to reconstruct the primary PTM pattern. A high-fidelity reconstruction, potentially 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 with antagonism. This is further supported empirically through observations from some recent experimental data CONCLUSIONS: Our work provides a computational model to quantify the effect of combinatorial histone PTMs in epigenetic inheritance. The fidelity of reconstruction of the primary histone PTM post-replication, is shown to be enhanced in the presence of antagonistic PTMs in the vicinity.