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.
Data availability
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.
Reviewing Editor
- Hugo J Bellen, Baylor College of Medicine, United States
Version history
- Received: November 15, 2019
- Accepted: April 15, 2020
- Accepted Manuscript published: April 16, 2020 (version 1)
- Version of Record published: May 11, 2020 (version 2)
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
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