Frequency-modulated nuclear localization bursts coordinate gene regulation

In yeast, the transcription factor Crz1 is dephosphorylated and translocates into the nucleus in response to extracellular calcium. Here we show, using time- lapse microscopy, that Crz1 exhibits short bursts of nuclear localization ( typically lasting 2 min) that occur stochastically in individual cells and propagate to the expression of downstream genes. Strikingly, calcium concentration controls the frequency, but not the duration, of localization bursts. Using an analytic model, we also show that this frequency modulation of bursts ensures proportional expression of multiple target genes across a wide dynamic range of expression levels, independent of promoter characteristics. We experimentally confirm this theory with natural and synthetic Crz1 target promoters. Another stress- response transcription factor, Msn2, exhibits similar, but largely uncorrelated, localization bursts under calcium stress suggesting that frequency- modulation regulation of localization bursts may be a general control strategy used by the cell to coordinate multi- gene responses to external signals.