Studies of individual living cells have revealed that many transcription factors activate in dynamic, and often stochastic, pulses within the same cell. However, it has remained unclear whether cells might exploit the dynamic interaction of these pulses to control gene expression. Here, using quantitative single-cell time-lapse imaging of Saccharomyces cerevisiae, we show that the pulsatile transcription factors Msn2 and Mig1 combinatorially regulate their target genes through modulation of their relative pulse timing. The activator Msn2 and repressor Mig1 showed pulsed activation in either a temporally overlapping or non-overlapping manner during their transient response to different inputs, with only the non-overlapping dynamics efficiently activating target gene expression. Similarly, under constant environmental conditions, where Msn2 and Mig1 exhibit sporadic pulsing, glucose concentration modulated the temporal overlap between pulses of the two factors. Together, these results reveal a time-based mode of combinatorial gene regulation. Regulation through relative signal timing is common in engineering and neurobiology, and these results suggest that it could also function broadly within the signalling and regulatory systems of the cell.
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Acknowledgements We thank U. Alon, R. Corral, R. Deshaies, A. Eldar, J. Garcia-Ojalvo, R. Kishony, A. Moses, G. Seelig, P. Swain, and members of the Elowitz laboratory for comments and feedback on the manuscript. We also thank the core sequencing facility at Caltech for help on RNA-Seq. This work was supported by the NIH (R01 GM079771B, R01 GM086793A), the NSF (Award no. 1547056), DARPA (HR0011-05-1-0057), and by the Gordon and Betty Moore Foundation through Grant GBMF2809 to the Caltech Programmable Molecular Technology Initiative. L.C. acknowledges the Ellison foundation for support.
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