Enhancer architecture sensitizes cell-specific responses to Notch gene dose via a bind and discard mechanism
- Cincinnati Children's Hospital Research Foundation, United States
- Tel Aviv University, Israel
- Cincinnati Children's Hospital Medical Center, United States
- University of Cincinnati, United States
- Emory University, United States
- Cincinnati Children's hospital, United States
Abstract
Notch pathway haploinsufficiency can cause severe developmental syndromes with highly variable penetrance. Currently, we have a limited mechanistic understanding of phenotype variability due to gene dosage. Here, we unexpectedly found that inserting an enhancer containing pioneer transcription factor sites coupled to Notch dimer sites can induce a subset of Notch haploinsufficiency phenotypes in Drosophila with wild type Notch gene dose. Using Drosophila genetics, we show that this enhancer induces Notch phenotypes in a Cdk8-dependent, transcription-independent manner. We further combined mathematical modeling with quantitative trait and expression analysis to build a model that describes how changes in Notch signal production versus degradation differentially impact cellular outcomes that require long versus short signal duration. Altogether, these findings support a 'bind and discard' mechanism in which enhancers with specific binding sites promote rapid Cdk8-dependent Notch turnover, and thereby reduce Notch-dependent transcription at other loci and sensitize tissues to gene dose based upon signal duration.
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All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Collin J Christensen
Funding
National Science Foundation (1715822)
- David Sprinzak
- Brian Gebelein
National Institutes of Health (CA163653)
- Raphael Kopan
National Institutes of Health (CA178974)
- Rhett A Kovall
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Kuang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Enhancer architecture sensitizes cell-specific responses to Notch gene dose via a bind and discard mechanism
eLife 9:e53659.
https://doi.org/10.7554/eLife.53659
