A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment
Kenneth KH Ng,
Mary A Yui,
Arnav Mehta,
Sharmayne Siu,
Blythe Irwin,
Shirley Pease,
Satoshi Hirose,
Michael B Elowitz,
Ellen V Rothenberg,
Hao Yuan Kueh
Affiliations
Kenneth KH Ng
Department of Bioengineering, University of Washington, Seattle, United States; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States; Department of Applied Physics, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, United States
Department of Bioengineering, University of Washington, Seattle, United States; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
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.
