PT  - JOURNAL ARTICLE
AU  - Kenneth K.H. Ng
AU  - Mary A. Yui
AU  - Arnav Mehta
AU  - Sharmayne Siu
AU  - Blythe Irwin
AU  - Shirley Pease
AU  - Satoshi Hirose
AU  - Michael B. Elowitz
AU  - Ellen V. Rothenberg
AU  - Hao Yuan Kueh
TI  - A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment
AID  - 10.1101/318675
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 318675
4099  - http://biorxiv.org/content/early/2018/05/10/318675.short
4100  - http://biorxiv.org/content/early/2018/05/10/318675.full
AB  - 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 cis-epigenetic mechanisms at individual gene loci. Here, we studied the activation of Bcl11b, which controls T-cell fate commitment. To disentangle cis and trans effects, we generated mice where two Bcl11b copies are tagged with distinguishable fluorescent proteins. Quantitative live microscopy of progenitors from these mice revealed that Bcl11b turned on after a stochastic delay averaging multiple days, which varied not only between cells but also between Bcl11b 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 trans-acting step stimulates expression from activated loci. These results show that developmental fate transitions can be controlled by stochastic cis-acting events on individual loci.