Ratio-based sensing of two transcription factors regulates the transit to differentiation

Cell state transitions are often triggered by large changes in the absolute concentrations of transcription factors and therefore large differences in the stoichiometric ratios between these factors. Whether cells can elicit state transitions using modest changes in the relative ratios of co-expressed factors is unclear. In this study we investigate how cells in the Drosophila eye resolve cell state transitions by quantifying the expression dynamics of the ETS transcription factors Pnt and Yan. We find that eye progenitor cells maintain a relatively constant ratio of Pnt/Yan protein despite expressing both proteins with pulsatile dynamics. A rapid and sustained two-fold increase in the Pnt/Yan ratio accompanies transitions to photoreceptor fates. Genetic perturbations that modestly disrupt the Pnt/Yan ratio produce fate transition defects consistent with the hypothesis that transitions are normally driven by a two-fold shift in the ratio. A biophysical model based on cooperative Yan-DNA binding coupled with non-cooperative Pnt-DNA binding illustrates how two-fold ratio changes could generate ultrasensitive changes in target gene transcription to drive fate transitions. In this way, coupling cell state transitions to the Pnt/Yan stoichiometric ratio sensitizes the system to modest fold-changes, conferring both robustness and ultrasensitivity to the developmental program.