title: Transcription factor competition allows embryonic stem cells to distinguish authentic signals from noise.
abstract: 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 (ES) cells achieves a robust response to differentiation cues but not to gene expression fluctuations. We engineered ES cells in which we could quantitatively ontrol the endogenous mechanism of neural differentiation through a light-inducible Brn2 transgene and monitor 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.
authors.affiliation: Center for Systems and Synthetic Biology, University of California, San Francisco; San Francisco, California, 94158. USA ; Department of Cellular and Molecular Pharmacology, University of California, San Francisco; San Francisco, California, 94158. USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Sokolik
authors.affiliation: Center for Systems and Synthetic Biology, University of California, San Francisco; San Francisco, California, 94158. USA.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Systems and Synthetic Biology, University of California, San Francisco; San Francisco, California, 94158. USA ; Department of Cellular and Molecular Pharmacology, University of California, San Francisco; San Francisco, California, 94158. USA.
authors.forename: David
authors.initials: D
authors.lastname: Bauer
authors.affiliation: Center for Systems and Synthetic Biology, University of California, San Francisco; San Francisco, California, 94158. USA ; Department of Cellular and Molecular Pharmacology, University of California, San Francisco; San Francisco, California, 94158. USA.
authors.forename: Jade
authors.initials: J
authors.lastname: McPherson
authors.affiliation: Center for Systems and Synthetic Biology, University of California, San Francisco; San Francisco, California, 94158. USA ; Department of Cellular and Molecular Pharmacology, University of California, San Francisco; San Francisco, California, 94158. USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Broeker
authors.affiliation: Center for Systems and Synthetic Biology, University of California, San Francisco; San Francisco, California, 94158. USA.
authors.forename: Graham
authors.initials: G
authors.lastname: Heimberg
authors.affiliation: Center for Systems and Synthetic Biology, University of California, San Francisco; San Francisco, California, 94158. USA.
authors.forename: Lei S
authors.initials: LS
authors.lastname: Qi
authors.affiliation: Center for Systems and Synthetic Biology, University of California, San Francisco; San Francisco, California, 94158. USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Sivak
authors.affiliation: Center for Systems and Synthetic Biology, University of California, San Francisco; San Francisco, California, 94158. USA ; Department of Cellular and Molecular Pharmacology, University of California, San Francisco; San Francisco, California, 94158. USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Thomson