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Frequency-modulated nuclear localization bursts coordinate gene regulation

Nature volumeΒ 455,Β pages 485–490 (2008)Cite this article

Abstract

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.

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Figure 1: Crz1 undergoes bursts of nuclear localization in response to calcium.
Figure 2: Calcium modulates the frequency, but not the duration, of Crz1 nuclear localization bursts.
Figure 3: Crz1 localization bursts are partially independent of other cellular processes and affect downstream gene expression.
Figure 4: Frequency- versus amplitude-modulation regulation of two hypothetical target genes, labelled A and B (schematic).
Figure 5: Frequency-modulated bursts coordinate gene expression.

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Acknowledgements

We thank M. Cyert for the CDRE and Crz1 mutant plasmids, K. Cunningham for the Crz1 overexpression plasmid pLE66, J. Stadler for the pGW845 FRET plasmid, S. Ramanathan for image analysis code, and K. Thorn, C.-L. Guo and L. LeBon for technical assistance. We thank U. Alon, M. Carlson, M. Cyert, H. Garcia, R. Kishony, G. Lahav, J.-G. Ojalvo, I. Riedel-Kruse, B. Shraiman, G. SΓΌel, members of the laboratory, and especially N. Friedman for discussions. L.C. is supported by the Beckman Fellows Program at Caltech. This work was supported by National Institutes of Health grants R01GM079771 and P50 GM068763 for National Centers of Systems Biology, and the Packard Foundation.

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Author notes

  1. Long Cai and Chiraj K. Dalal: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Biology and Department of Applied Physics, Howard Hughes Medical Institute, California Institute of Technology, M/C 114-96, Pasadena, California 91125, USA,

    Long Cai,Β Chiraj K. DalalΒ &Β Michael B. Elowitz

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Correspondence to Michael B. Elowitz.

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This file contains a time-lapse fluorescence movie of Crz1-GFP cells with 150 mM Ca2+ added at the beginning of the movie. (MOV 5739 kb)

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Cai, L., Dalal, C. & Elowitz, M. Frequency-modulated nuclear localization bursts coordinate gene regulation. Nature 455, 485–490 (2008). https://doi.org/10.1038/nature07292

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