Optogenetic Control Reveals Differential Promoter Interpretation of Transcription Factor Nuclear Translocation Dynamics

Gene expression is thought to be affected not only by the concentration of transcription factors (TFs) but also the dynamics of their nuclear translocation. Testing this hypothesis requires direct control of TF dynamics. Here, we engineer CLASP, an optogenetic tool for rapid and tunable translocation of a TF of interest. Using CLASP fused to Crz1, we observe that, for the same integrated concentration of nuclear TF over time, changing input dynamics changes target gene expression: pulsatile inputs yield higher expression than continuous inputs, or vice versa, depending on the target gene. Computational modeling reveals that a dose-response saturating at low TF input can yield higher gene expression for pulsatile versus continuous input, and that multi-state promoter activation can yield the opposite behavior. Our integrated tool development and modeling approach characterize promoter responses to Crz1 nuclear translocation dynamics, extracting quantitative features that may help explain the differential expression of target genes. [Display omitted] •CLASP, an optogenetic tool, translocates TFs to the nucleus with minute-level resolution•Crz1 genes show different expression for pulsatile or continuous Crz1-CLASP inputs•Modeling reveals quantitative promoter features required for TF input decoding•Two- and three-state promoter models explain differential gene expression CLASP is a modular optogenetic strategy to control the nuclear localization of transcription factors (TFs) and elicit gene expression from their cognate promoters. CLASP control of Crz1 nuclear localization, coupled with computational modeling, revealed how promoters can differentially decode dynamic transcription factor signals. The integrated strategy of CLASP development and modeling presents a generalized approach to causally investigate the transcriptional consequences of dynamic TF nuclear shuttling.