title: Dynamic model for the coordination of two enhancers of broad by EGFR signaling.
abstract: Although it is widely appreciated that a typical developmental control gene is regulated by multiple enhancers, coordination of enhancer activities remains poorly understood. We propose a mechanism for such coordination in Drosophila oogenesis, when the expression of the transcription factor Broad (BR) evolves from a uniform to a two-domain pattern that prefigures the formation of two respiratory eggshell appendages. This change reflects sequential activities of two enhancers of the br gene, early and late, both of which are controlled by the epidermal growth factor receptor (EGFR) pathway. The late enhancer controls br in the appendage-producing cells, but the function of the early enhancer remained unclear. We found that the early enhancer is essential for the activity of the late enhancer and induction of eggshell appendages. This requirement can be explained by a mechanism whereby the BR protein produced by the early enhancer protects the late enhancer from EGFR-dependent repression. We illustrate this complex mechanism using a computational model that correctly predicts the wild-type dynamics of BR expression and its response to genetic perturbations.
authors.affiliation: Department of Chemical and Biological Engineering and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544.
authors.forename: Lily S
authors.initials: LS
authors.lastname: Cheung
authors.forename: David S A
authors.initials: DS
authors.lastname: Simakov
authors.forename: Alisa
authors.initials: A
authors.lastname: Fuchs
authors.forename: George
authors.initials: G
authors.lastname: Pyrowolakis
authors.forename: Stanislav Y
authors.initials: SY
authors.lastname: Shvartsman
mesh_terms: D000818:Animals; D019295:Computational Biology; D004330:Drosophila / Q000502:physiology*; D029721:Drosophila Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D008954:Models, Biological; D009866:Oogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C102117:Br protein, Drosophila; D029721:Drosophila Proteins; D014157:Transcription Factors; D066246:ErbB Receptors
keywords: mathematical modeling; morphogen gradients