A conserved role for Snail as a potentiator of active transcription

  1. Eileen E.M. Furlong2,8
  1. 1Institute of Genetics, University of Cologne, 50674 Cologne, Germany;
  2. 2European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany;
  3. 3Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria;
  4. 4Department of Biology, Brandeis University, Waltham, Massachusetts 02453, USA;
  5. 5Department of Biology, University of Rochester, Rochester, New York 14627, USA
    1. 6 These authors contributed equally to this work.

    • 7 Present address: Berlin Institute for Medical Systems Biology, Max Delbrück Centrum, 13092 Berlin, Germany

    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

    Footnotes

    • Received September 17, 2013.
    • Accepted December 10, 2013.

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