Mixing, competence, and commitment set the stability of cell identity

Cells maintain their identities in the face of molecular noise, yet can change them rapidly when cued. Here, we treat this tension as a problem in the control of a stochastic system. We represent a cell identity as a set of molecular configurations, or microstates, among which cells undergo stochastic transitions, and measure its stability by the effective rate of commitment to another identity, using a Markov model in which committed cells are removed. Mixing, competence, and commitment provide three channels for tuning this rate. They govern microstate transitions, how commitment is distributed among microstates, and the overall speed of commitment, respectively. Control over the effective commitment rate is shared between commitment and mixing in proportions that always sum to one. Interventions with the same effective commitment rate cannot be told apart by survival alone but, given the microstate transition rates, can be distinguished by the fraction of cells in each microstate or by how quickly cells sorted on permissive microstates commit. When competence varies in time, pulsed commitment signalling commits more cells than sustained signalling of equal dose, by an amount that grows with the depth of that variation, whereas with constant competence pulsing gains nothing in the models we studied. This suggests a possible function for pulsatile signalling, such as that of ERK, which the experiments we propose could test. Finally, reanalysing single-cell imaging of mouse embryonic stem cells leaving naive pluripotency, we estimate that cells take about as long to acquire competence as they then wait to commit, and we specify experiments to identify which channel drives this exit.