Control of T-Cell Lineage Specification By a Slow, Stochastic Epigenetic Switch

Developmental cell fate decisions require switch-like, irreversible activation of the expression of fate-specifying genes. In higher eukaryotes, gene activation is accompanied by dramatic changes to the chemical or physical states of gene loci on chromosomes. However, how these epigenetic mechanisms control developmental gene activation dynamics remains unclear. Here we studied the activation dynamics of Bcl11b, a gene essential for T-cell fate commitment. By separately following the regulation of two chromosomal Bcl11b copies in the same cell, we found that Bcl11b activation requires a stochastic, irreversible switch of its chromosomal locus from an inactive to active state. This cis-acting switch triggers with a slow multi-day rate constant controlled by a distal enhancer, and works in parallel with a Notch signaling-dependent step to enable Bcl11b expression. These results establish clear evidence that an epigenetic switch controls a mammalian fate decision, and demonstrate how simultaneous tracking of two alleles in individual living cells can reveal epigenetic mechanisms of cell fate control.