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Combinatorial gene regulation by modulation of relative pulse timing

Lin, Yihan and Sohn, Chang Ho and Dalal, Chiraj K. and Cai, Long and Elowitz, Michael B. (2015) Combinatorial gene regulation by modulation of relative pulse timing. Nature, 527 (7576). pp. 54-58. ISSN 0028-0836. PMCID PMC4870307. doi:10.1038/nature15710. https://resolver.caltech.edu/CaltechAUTHORS:20150805-144646254

[img] PDF - Accepted Version
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[img] PDF (Supplementary Discussion, Supplementary Note, Supplementary References and Supplementary Table 1) - Supplemental Material
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[img] Video (QuickTime) (Video 1: Single-cell videos of Msn2-mKO2 and Mig1-mCherry in response to sudden reduction in glucose concentration) - Supplemental Material
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[img] Video (QuickTime) (Video 2: Three-color single-cell videos of the synthetic combinatorial promoter strain in response to NaCl) - Supplemental Material
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[img] Video (QuickTime) (Video 3: Three-color single-cell videos of the synthetic combinatorial promoter strain in response to ethanol) - Supplemental Material
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[img] Video (QuickTime) (Video 4: Three-color single-cell videos of synthetic combinatorial promoter strain under constant glucose conditions) - Supplemental Material
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[img] Video (QuickTime) (Video 5: Three-color single-cell videos of natural GSY1 combinatorial promoter strain under constant glucose conditions) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 1: Single-cell analysis of relative pulse timing modulation by stress identity during transient response) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 2: Additional data and analysis for transient stress responses) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 3: Example 3-colour single-cell traces under steady-state conditions, and schematic diagram of pulse-triggered averaging analysis) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 4: Pulse-triggered averaging analysis for control promoters and for delayed pulse timing events) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 5: Analysis of mean gene expression dependence on time interval (continuous relative timing) between Msn2 and Mig1 pulses) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 6: Example single-cell nuclear localization traces for different constant glucose conditions) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 7: Characterization of Msn2 and Mig1 pulses and average cross-correlation functions between Msn2 and Mig1 in individual cells across different constant glucose concentrations) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 8: Further characterization of relative pulse timing modulation under steady-state conditions) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 9: Additional effects of stress level and type on transient and steady-state responses) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 10: A role for Glc7 in active relative pulse timing modulation under constant glucose conditions and functional aspect of relative pulse timing modulation) - Supplemental Material
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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/nature15710DOIArticle
http://rdcu.be/et29PublisherFree ReadCube access
http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE71712Related ItemRNA-Seq data
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870307/PubMed CentralArticle
ORCID:
AuthorORCID
Lin, Yihan0000-0002-2763-5538
Sohn, Chang Ho0000-0002-7585-1841
Dalal, Chiraj K.0000-0002-3624-8409
Cai, Long0000-0002-7154-5361
Elowitz, Michael B.0000-0002-1221-0967
Additional Information:© 2015 Macmillan Publishers Limited. Received 02 January 2015; Accepted 04 September 2015; Published online 14 October 2015. 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 themanuscript. 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. Author Contributions: Y.L. and M.B.E. designed experiments. Y.L. performed experiments and analysed data with input from all authors. C.K.D. and L.C. initially observed the correlation between Msn2 and Mig1 dynamics and C.H.S. conducted preliminary analysis of target gene expression. M.B.E. supervised research. Y.L. and M.B.E. wrote the manuscript with input from all authors. The authors declare no competing financial interests. RNA-Seq data have been deposited at Gene Expression Omnibus (GEO) under the accession code GSE71712.
Funders:
Funding AgencyGrant Number
NIHR01 GM079771B
NIHR01 GM086793A
NSFMCB-1547056
Defense Advanced Research Projects Agency (DARPA)HR0011-05-1-0057
Gordon and Betty Moore FoundationGBMF2809
Ellison Medical FoundationUNSPECIFIED
Issue or Number:7576
PubMed Central ID:PMC4870307
DOI:10.1038/nature15710
Record Number:CaltechAUTHORS:20150805-144646254
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150805-144646254
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:59247
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:19 Oct 2015 18:20
Last Modified:19 May 2022 17:45

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