| Autor: |
Yi Kuang, Ohad Golan, Kristina Preusse, Brittany Cain, Collin J Christensen, Joseph Salomone, Ian Campbell, FearGod V Okwubido-Williams, Matthew R Hass, Zhenyu Yuan, Nathanel Eafergan, Kenneth H Moberg, Rhett A Kovall, Raphael Kopan, David Sprinzak, Brian Gebelein |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
eLife, Vol 9 (2020) |
| Druh dokumentu: |
article |
| ISSN: |
2050-084X |
| DOI: |
10.7554/eLife.53659 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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