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NF-κB memory coordinates transcriptional responses to dynamic inflammatory stimuli

View ORCID ProfileAndrew G. Wang, View ORCID ProfileMinjun Son, Nicholas Thom, View ORCID ProfileSavaş Tay
doi: https://doi.org/10.1101/2022.01.14.476099
Andrew G. Wang
1Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
2Medical Scientist Training Program, University of Chicago, Chicago, IL 60637, USA
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Minjun Son
1Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
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Nicholas Thom
1Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
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Savaş Tay
1Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
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  • ORCID record for Savaş Tay
  • For correspondence: tays@uchicago.edu
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Abstract

Many scenarios in cellular communication requires cells to interpret multiple dynamic signals. It is unclear how exposure to immune stimuli alters transcriptional responses to subsequent stimulus under inflammatory conditions. Using high-throughput microfluidic live cell analysis, we systematically profiled the NF-κB response to different signal sequences in single cells. We found that NF-κB dynamics stores the history of signals received by cells: depending on the dose and type of prior pathogenic and cytokine signal, the NF-κB response to subsequent stimuli varied widely, from no response to full activation. Using information theory, we revealed that these stimulus-dependent changes in the NF-κB response encode and reflect information about the identity and dose of the prior stimulus. Small-molecule inhibition, computational modeling, and gene expression profiling show that this encoding is driven by stimulus-dependent engagement of negative feedback modules. These results provide a model for how signal transduction networks process sequences of inflammatory stimuli to coordinate cellular responses in complex dynamic environments.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://github.com/tay-lab/Sequential_NF-kB_stim

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 16, 2022.
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NF-κB memory coordinates transcriptional responses to dynamic inflammatory stimuli
Andrew G. Wang, Minjun Son, Nicholas Thom, Savaş Tay
bioRxiv 2022.01.14.476099; doi: https://doi.org/10.1101/2022.01.14.476099
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NF-κB memory coordinates transcriptional responses to dynamic inflammatory stimuli
Andrew G. Wang, Minjun Son, Nicholas Thom, Savaş Tay
bioRxiv 2022.01.14.476099; doi: https://doi.org/10.1101/2022.01.14.476099

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