Dynamic model for the coordination of two enhancers of broad by EGFR signaling

Edited by Michael Levine, University of California, Berkeley, CA, and approved September 23, 2013 (received for review March 11, 2013)
October 14, 2013
110 (44) 17939-17944

Significance

Temporal regulation of a typical developmental control gene depends on multiple enhancers, which makes it important to understand how enhancers coordinate their activities in time. We describe a mechanism for such coordination in Drosophila oogenesis, where the expression of the transcription factor Broad depends on sequential activities of two enhancers. The early enhancer is essential for activity of the late one. To explain this requirement, we propose a mechanism based on a network with feedforward and feedback loops. This network interprets and modulates the epidermal growth factor receptor (EGFR) signaling gradient that controls both enhancers. Experiments and computational modeling show that understanding Broad expression is impossible without simultaneously considering two enhancers, a dynamic gradient, and a network with extracellular and intracellular components.

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.

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Acknowledgments

We are indebted to Trudi Schüpbach, Miriam Osterfield, Nir Yakoby, and Jeremiah Zartman for helpful discussions and comments on the manuscript. We thank Eric Wieschaus for the use of SEM and Miriam Osterfield for help with eggshell images. We thank the TRiP at Harvard Medical School (National Institutes of Health/National Institute of General Medical Sciences Grant R01-GM084947) for providing the transgenic RNAi fly stocks used in this study. This work was supported by Human Frontiers Science Program Grant RGP0052/2009-C and by National Institutes of Health Grant P50-GM071508.

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 110 | No. 44
October 29, 2013
PubMed: 24127599

Classifications

Submission history

Published online: October 14, 2013
Published in issue: October 29, 2013

Keywords

  1. morphogen gradients
  2. mathematical modeling

Acknowledgments

We are indebted to Trudi Schüpbach, Miriam Osterfield, Nir Yakoby, and Jeremiah Zartman for helpful discussions and comments on the manuscript. We thank Eric Wieschaus for the use of SEM and Miriam Osterfield for help with eggshell images. We thank the TRiP at Harvard Medical School (National Institutes of Health/National Institute of General Medical Sciences Grant R01-GM084947) for providing the transgenic RNAi fly stocks used in this study. This work was supported by Human Frontiers Science Program Grant RGP0052/2009-C and by National Institutes of Health Grant P50-GM071508.

Notes

This article is a PNAS Direct Submission.

Authors

Affiliations

Lily S. Cheung1
Department of Chemical and Biological Engineering and
Lewis–Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544;
David S. A. Simakov1
Department of Earth and Planetary Sciences, Harvard University, Cambridge, MA 02142; and
Alisa Fuchs
Institute for Biology I and
BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs—University of Freiburg, 79104 Freiburg, Germany
George Pyrowolakis
Institute for Biology I and
BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs—University of Freiburg, 79104 Freiburg, Germany
Stanislav Y. Shvartsman2 [email protected]
Department of Chemical and Biological Engineering and
Lewis–Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544;

Notes

2
To whom correspondence should be addressed. E-mail: [email protected].
Author contributions: L.S.C., G.P., and S.Y.S. designed research; L.S.C., D.S.A.S., A.F., G.P., and S.Y.S. performed research; L.S.C., D.S.A.S., A.F., G.P., and S.Y.S. analyzed data; and L.S.C., D.S.A.S., G.P., and S.Y.S. wrote the paper.
1
L.S.C. and D.S.A.S. contributed equally to this work.

Competing Interests

The authors declare no conflict of interest.

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    Dynamic model for the coordination of two enhancers of broad by EGFR signaling
    Proceedings of the National Academy of Sciences
    • Vol. 110
    • No. 44
    • pp. 17601-18024

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