Kuang, Y., Golan, O., Preusse, K., Cain, B., Christensen, C.J., Salomone, J., Campbell, I., Okwubido-Williams, F.V., Hass, M.R., Yuan, Z., Eafergan, N., Moberg, K.H., Kovall, R.A., Kopan, R., Sprinzak, D., Gebelein, B. (2020). Enhancer architecture sensitizes cell specific responses to Notch gene dose via a bind and discard mechanism.  eLife 9(): e53659.

FBrf0245600

Research paper

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.

PMC7213981 (PMC) (EuropePMC)