Temporal scaling in developmental gene networks by epigenetic timing control

Abstract

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.

Tunable, division-independent control of gene activation timing by a polycomb switch

“…The methylation-compaction switching mechanism could underlie diverse cell-autonomous timers that have been observed to work independently of cell division ( Burton et al, 1999 ; Gao et al, 1997 ; Heinzel et al, 2017 ; Li et al, 2019 ; Okamoto et al, 2016 ; Osmond, 1991 ; Otani et al, 2016 ). Measuring elapsed time independently of cell division could enable unique functions, including operation in non-dividing cells and constancy amid changes to cell proliferation, which could allow for tunable population size control, an idea we explore in a separate study ( Nguyen et al, 2019 ). Our simulations revealed that such division-independent timing control requires active turnover of H3K27me3 and nucleosome compaction dynamics to be rapid compared to the cell cycle length ( Methods S1 ; Figure S5F ).…”