A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment.

Cell fate decisions occur through the switch-like, irreversible activation of fate-specifying genes. These activation events are often assumed to be tightly coupled to changes in upstream transcription factors, but could also be constrained by -epigenetic mechanisms at individual gene loci. Here, we studied the activation of , which controls T-cell fate commitment. To disentangle and effects, we generated mice where two copies are tagged with distinguishable fluorescent proteins. Quantitative live microscopy of progenitors from these mice revealed that turned on after a stochastic delay averaging multiple days, which varied not only between cells but also between alleles within the same cell. Genetic perturbations, together with mathematical modeling, showed that a distal enhancer controls the rate of epigenetic activation, while a parallel Notch-dependent -acting step stimulates expression from activated loci. These results show that developmental fate transitions can be controlled by stochastic -acting events on individual loci.