Transcription Factor Competition Allows Embryonic Stem Cells to Distinguish Authentic Signals from Noise

Stem cells occupy variable environments where they must distinguish stochastic fluctuations from developmental cues. Here, we use optogenetics to investigate how the pluripotency network in embryonic stem cells (ESCs) achieves a robust response to differentiation cues but not to gene expression fluctuations. We engineered mouse ESCs to allow quantitative control over the endogenous mechanism of neural differentiation through a light-inducible Brn2 transgene and monitored differentiation status through a genome-integrated Nanog-GFP reporter. By exposing cells to pulses of Brn2, we find that the pluripotency network rejects Brn2 inputs that are below specific magnitude or duration thresholds, but allows rapid differentiation when both thresholds are satisfied. The filtering properties of the network arise through its positive feedback architecture and the intrinsic half-life of Nanog, which determines the duration threshold in the network. Together our results suggest that the dynamic properties of positive feedback networks might determine how inputs are classified as signal or noise by stem cells.