A Slow, Stochastic Epigenetic Switch Controls a Mammalian Developmental Decision

Cell fate decisions require the irreversible, switch-like activation in the expression of fate-specifying genes, properly regulated in time. In mammalian cells, switches in gene activity are thought to involve epigenetic mechanisms – changes in chromosomal states heritable across cell division. However, how epigenetic mechanisms control gene activation dynamics remain unclear. Here, we investigated the role for epigenetic mechanisms in turning on the expression of Bcl11b, a gene encoding an essential T-cell transcription factor. Using quantitative live-cell imaging, we simultaneously analyzed the regulation of the two chromosomal copies of Bcl11b in the same cell, each tagged with a different colored fluorescent protein. Strikingly, the two copies of Bcl11b switched on asynchronously in a stochastic and independent manner in clonal lineages of dividing progenitors, maintaining different activity states in the same cell across many divisions. Stochastic activation rates were controlled by cis-regulatory elements on the Bcl11b locus, and dropped drastically after a critical time window in development. Our results establish definitive evidence that an epigenetic switch controls a mammalian cell fate decision, and outline a general approach for quantitative, mechanistic investigation of epigenetic regulatory dynamics in living cells.