title: Combinatorial gene regulation by modulation of relative pulse timing.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California 91125, USA.|Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Chang Ho
authors.initials: CH
authors.lastname: Sohn
authors.affiliation: Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California 91125, USA.|Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Chiraj K
authors.initials: CK
authors.lastname: Dalal
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Cai
authors.affiliation: Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California 91125, USA.|Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Elowitz
mesh_terms: D004268:DNA-Binding Proteins / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction; D059010:Single-Cell Analysis; D013997:Time Factors; D059008:Time-Lapse Imaging; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C085976:MIG1 protein, S cerevisiae; C081935:MSN2 protein, S cerevisiae; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D005947:Glucose