A population model reveals a surprising role of stochastic cell division in epigenetic memory systems

Epigenetic memory systems store transient environmental signals in bacteria in specific DNA methylation patterns. Synthetic zinc finger protein (ZnF4) binds to the DNA in a methylation-dependent manner and represses the expression of the DNA methyltransferase CcrM. The mechanisms ensuring long-term ON-state stability remain unclear. Measurements showed a gradual shift of cell populations from ON to OFF starting after four days of cultivation. We use a hybrid modeling approach integrating flow cytometry data and bulk DNA methylation measurements to test the hypothesis that stochastic cell division is a key factor in this transition. Interestingly, model parameters cluster into two groups with opposite effects of cell division rates on ON-state stability. Experiments show that faster cell division increases memory stability-an initially unexpected result. Model simulations provide a potential explanation for this observation and deepen our understanding of the mechanisms and timing of the ON/OFF switch in individual cells.