1. Developmental Biology
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Enhancer architecture sensitizes cell-specific responses to Notch gene dose via a bind and discard mechanism

  1. Yi Kuang
  2. Ohad Golan
  3. Kristina Preusse
  4. Brittany Cain
  5. Collin J Christensen
  6. Joseph Salomone
  7. Ian Campbell
  8. FearGod V Okwubido-Williams
  9. Matthew R Hass
  10. Zhenyu Yuan
  11. Nathanel Eafergan
  12. Kenneth H Moberg
  13. Rhett A Kovall
  14. Raphael Kopan  Is a corresponding author
  15. David Sprinzak  Is a corresponding author
  16. Brian Gebelein  Is a corresponding author
  1. Cincinnati Children's Hospital Research Foundation, United States
  2. Tel Aviv University, Israel
  3. Cincinnati Children's Hospital Medical Center, United States
  4. University of Cincinnati, United States
  5. Emory University, United States
  6. Cincinnati Children's hospital, United States
Research Article
  • Cited 2
  • Views 1,568
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Cite this article as: eLife 2020;9:e53659 doi: 10.7554/eLife.53659

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.

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Author details

  1. Yi Kuang

    Graduate Program in Molecular and Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1509-3620

  2. Ohad Golan

    Biochemistry, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.

  3. Kristina Preusse

    Pediatrics - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Brittany Cain

    Engineering, University of Cincinnati, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Collin J Christensen

    Pediatrics - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6932-5554

  6. Joseph Salomone

    Pediatrics - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Ian Campbell

    Engineering, University of Cincinnati, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. FearGod V Okwubido-Williams

    Engineering, University of Cincinnati, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Matthew R Hass

    Pediatrics - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Zhenyu Yuan

    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Nathanel Eafergan

    Department of Biochemistry and Molecular Biology, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.

  12. Kenneth H Moberg

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.

  13. Rhett A Kovall

    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0520-1613

  14. Raphael Kopan

    Division of Developmental Biology, Cincinnati Children's hospital, Cincinnati, United States
    For correspondence
    raphael.kopan@cchmc.org
    Competing interests
    The authors declare that no competing interests exist.

  15. David Sprinzak

    Department of Biochemistry and Molecular Biology, Tel Aviv University, Tel Aviv, Israel
    For correspondence
    davidsp@post.tau.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6776-6957

  16. Brian Gebelein

    Pediatrics - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    For correspondence
    brian.gebelein@cchmc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9791-9061

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

  1. Hugo J Bellen, Baylor College of Medicine, United States

Publication history

  1. Received: November 15, 2019
  2. Accepted: April 15, 2020
  3. Accepted Manuscript published: April 16, 2020 (version 1)
  4. 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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