Enhancer architecture sensitizes cell specific responses to Notch gene dose via a bind and discard mechanism

Yi Kuang, Ohad Golan, Kristina Preusse, Brittany Cain, Collin J. Christensen, Joseph Salomone, Ian Campbell, Feargod V. Okwubido-Williams, Matthew R. Hass, Zhenyu Yuan, Natanel Eafergan, Kenneth H. Moberg, Rhett A. Kovall, Raphael Kopan, David Sprinzak, Brian Gebelein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere53659
JournaleLife
Volume9
DOIs
StatePublished - Apr 2020

Keywords

  • Cdk8-Kinase module
  • Degradation
  • Drosophila
  • Enhancer
  • Haploinsufficiency
  • Notch signaling
  • Transcription factor binding sites

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