Polyphasic feedback enables tunable cellular timers

Cellular 'timers' provide an important function in living cells [1]. Timers help cells defer their responses to stimuli, often for time intervals extending over multiple cell cycles (Figure 1A, left). For example, mammalian oligodendrocyte precursors typically proliferate for ∼7 divisions before differentiating during neural development [2]. The bacterium Bacillus subtilis can respond to sudden nutrient limitation by transforming into a dormant spore after ∼5 cell cycles [3]. Timers can balance proliferation with differentiation to control the sizes of various cell populations. Some timers appear to operate in a largely cell-autonomous fashion, but the underlying genetic circuit mechanisms that enable this remain poorly understood. Protein dilution poses stringent challenges to timer circuits by continually diluting out timer components in proliferating cells ( Figure 1A, right). Recent work suggests that pulsatile or oscillatory dynamics can facilitate timer functions 3 and 4. Here, we show how polyphasic positive feedback — a pulsed architecture that breaks a feedback signal into temporally distinct phases — counteracts protein dilution to facilitate timer behavior.