Temporal scaling in developmental gene networks by epigenetic timing control

Summary During development, progenitors follow defined temporal schedules for differentiation, to form organs and body plans with precise sizes and proportions. Across diverse contexts, these developmental schedules are encoded by autonomous timekeeping mechanisms in single cells. These autonomous timers not only operate robustly over many cell generations, but can also operate at different speeds in different species, enabling proportional scaling of temporal schedules and population sizes. By combining mathematical modeling with live-cell measurements, we elucidate the mechanism of a polycomb-based epigenetic timer, that delays activation of the T-cell commitment regulator Bcl11b to facilitate progenitor expansion. This mechanism generates activation delays that are independent of cell cycle duration, and are tunably controlled by transcription factors and epigenetic modifiers. When incorporated into regulatory gene networks, this epigenetic timer enables progenitors to set scalable temporal schedules for flexible size control. These findings illuminate how evolution may set and adjust developmental speed in multicellular organisms.