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Gene regulation gravitates towards either addition or multiplication when combining the effects of two signals

View ORCID ProfileEric M. Sanford, View ORCID ProfileBenjamin L. Emert, View ORCID ProfileAllison Coté, View ORCID ProfileArjun Raj
doi: https://doi.org/10.1101/2020.05.26.116962
Eric M. Sanford
2Perelman School of Medicine, University of Pennsylvania
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Benjamin L. Emert
2Perelman School of Medicine, University of Pennsylvania
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Allison Coté
2Perelman School of Medicine, University of Pennsylvania
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Arjun Raj
1Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania
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  • For correspondence: arjunrajlab@gmail.com
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Abstract

Signals often ultimately affect the transcription of genes, and often, two different signals can affect the transcription of the same gene. In such cases, it is natural to ask how the combined transcriptional response compares to the individual responses. Mechanistic models can predict a range of combined responses, with the most commonly applied models predicting additive or multiplicative responses, but systematic genome-wide evaluation of these predictions are not available. Here, we performed a comprehensive analysis of the transcriptional response of human MCF-7 cells to two different signals (retinoic acid and TGF-β), applied individually and in combination. We found that the combined responses exhibited a range of behaviors, but clearly favored both additive and multiplicative combined transcriptional responses. We also performed paired chromatin accessibility measurements to measure putative transcription factor occupancy at regulatory elements near these genes. We found that increases in chromatin accessibility were largely additive, meaning that the combined accessibility response was the sum of the accessibility responses to each signal individually. We found some association between super-additivity of accessibility and multiplicative or super-multiplicative combined transcriptional responses, while sub-additivity of accessibility associated with additive transcriptional responses. Our findings suggest that mechanistic models of combined transcriptional regulation must be able to reproduce a range of behaviors.

Competing Interest Statement

AR receives royalties related to Stellaris RNA FISH probes. All other authors declare no competing interests.

Footnotes

  • We revised the manuscript in response to the reviews that were shared by eLife's preprint review service. Highlights of our revision include (1) A greatly expanded analysis of the c-value distribution, showing more rigorously that there are indeed two peaks that correspond to additive and multiplicative behavior. (2) An analysis of cross-activation between the two signals using new immunofluorescence data, showing minimal cross-activation. (3) More explanatory diagrams and equations throughout the manuscript, as suggested by the reviewers.

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 4.0 International license.
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Posted October 27, 2020.
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Gene regulation gravitates towards either addition or multiplication when combining the effects of two signals
Eric M. Sanford, Benjamin L. Emert, Allison Coté, Arjun Raj
bioRxiv 2020.05.26.116962; doi: https://doi.org/10.1101/2020.05.26.116962
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Gene regulation gravitates towards either addition or multiplication when combining the effects of two signals
Eric M. Sanford, Benjamin L. Emert, Allison Coté, Arjun Raj
bioRxiv 2020.05.26.116962; doi: https://doi.org/10.1101/2020.05.26.116962

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