Theory of epigenetic switching due to stochastic histone mark loss during DNA replication

Abstract

How much information does a cell inherit from its ancestors beyond its genetic sequence? What are the epigenetic mechanisms that allow this? Despite the rise in available epigenetic data, how such information is inherited through the cell cycle is still not fully understood. Here, we develop and analyse a simple mathematical model for histone-based epigenetic information that describes how daughter cells can recapitulate the gene expression profiles of their parent. We consider the dynamics of histone modifications during the cell cycle deterministically but also incorporate the largest stochastic element: DNA replication, where histones are randomly distributed between the two daughter DNA strands. This hybrid stochastic-deterministic approach enables an analytic derivation of the switching rate, i.e., the frequency of loss-of-memory events due to replication. While retaining great simplicity, the model can recapitulate experimental switching rate data, establishing its biological importance as a framework to quantitatively study epigenetic inheritance.