A conserved role for Snail as a potentiator of active transcription
- Martina Rembold1,6,
- Lucia Ciglar2,6,
- J. Omar Yáñez-Cuna3,
- Robert P. Zinzen2,7,
- Charles Girardot2,
- Ankit Jain4,
- Michael A. Welte4,5,
- Alexander Stark3,
- Maria Leptin1,8 and
- Eileen E.M. Furlong2,8
- 1Institute of Genetics, University of Cologne, 50674 Cologne, Germany;
- 2European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany;
- 3Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria;
- 4Department of Biology, Brandeis University, Waltham, Massachusetts 02453, USA;
- 5Department of Biology, University of Rochester, Rochester, New York 14627, USA
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↵6 These authors contributed equally to this work.
Abstract
The transcription factors of the Snail family are key regulators of epithelial–mesenchymal transitions, cell morphogenesis, and tumor metastasis. Since its discovery in Drosophila ∼25 years ago, Snail has been extensively studied for its role as a transcriptional repressor. Here we demonstrate that Drosophila Snail can positively modulate transcriptional activation. By combining information on in vivo occupancy with expression profiling of hand-selected, staged snail mutant embryos, we identified 106 genes that are potentially directly regulated by Snail during mesoderm development. In addition to the expected Snail-repressed genes, almost 50% of Snail targets showed an unanticipated activation. The majority of “Snail-activated” genes have enhancer elements cobound by Twist and are expressed in the mesoderm at the stages of Snail occupancy. Snail can potentiate Twist-mediated enhancer activation in vitro and is essential for enhancer activity in vivo. Using a machine learning approach, we show that differentially enriched motifs are sufficient to predict Snail's regulatory response. In silico mutagenesis revealed a likely causative motif, which we demonstrate is essential for enhancer activation. Taken together, these data indicate that Snail can potentiate enhancer activation by collaborating with different activators, providing a new mechanism by which Snail regulates development.
Keywords
- transcription factor
- Snail
- Twist
- repression
- activation
- spatiotemporal gene expression
- Drosophila embryogenesis
Footnotes
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↵8 Corresponding authors
E-mail furlong{at}embl.de
E-mail mleptin{at}uni-koeln.de
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.230953.113.
- Received September 17, 2013.
- Accepted December 10, 2013.
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