Coupling of DNA Replication and Negative Feedback Controls Gene Expression for Cell-Fate Decisions

Cellular decision-making arises from the expression of genes along a regulatory cascade, which leads to a choice between distinct phenotypic states. DNA dosage variations, often introduced by replication, can significantly affect gene expression to ultimately bias decision outcomes. The bacteriophage lambda system has long served as a paradigm for cell-fate determination, yet the effect of DNA replication remains largely unknown. Here, through single-cell studies and mathematical modeling we show that DNA replication drastically boosts cI expression to allow lysogenic commitment by providing more templates. Conversely, expression of CII, the upstream regulator of cI, is surprisingly robust to DNA replication due to the negative autoregulation of the Cro repressor. Our study exemplifies how living organisms can not only utilize DNA replication for gene expression control but also implement mechanisms such as negative feedback to allow the expression of certain genes to be robust to dosage changes resulting from DNA replication.