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

Abstract

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 <i>cis</i>-epigenetic mechanisms at individual gene loci. Here, we studied the activation of <i>Bcl11b</i>, which controls T-cell fate commitment. To disentangle <i>cis</i> and <i>trans</i> effects, we generated mice where two <i>Bcl11b</i> copies are tagged with distinguishable fluorescent proteins. Quantitative live microscopy of progenitors from these mice revealed that <i>Bcl11b</i> turned on after a stochastic delay averaging multiple days, which varied not only between cells but also between <i>Bcl11b</i> 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 <i>trans</i>-acting step stimulates expression from activated loci. These results show that developmental fate transitions can be controlled by stochastic <i>cis</i>-acting events on individual loci.