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.
Article and author information
Author details
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
Publication 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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