TY - JOUR TI - Enhancer architecture sensitizes cell specific responses to Notch gene dose via a bind and discard mechanism AU - Kuang, Yi AU - Golan, Ohad AU - Preusse, Kristina AU - Cain, Brittany AU - Christensen, Collin J AU - Salomone, Joseph AU - Campbell, Ian AU - Okwubido-Williams, FearGod V AU - Hass, Matthew R AU - Yuan, Zhenyu AU - Eafergan, Nathanel AU - Moberg, Kenneth H AU - Kovall, Rhett A AU - Kopan, Raphael AU - Sprinzak, David AU - Gebelein, Brian A2 - Bellen, Hugo J A2 - Walczak, Aleksandra M VL - 9 PY - 2020 DA - 2020/04/16 SP - e53659 C1 - eLife 2020;9:e53659 DO - 10.7554/eLife.53659 UR - https://doi.org/10.7554/eLife.53659 AB - 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. KW - Notch signaling KW - Cdk8-Kinase module KW - enhancer KW - transcription factor binding sites KW - degradation KW - haploinsufficiency JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -