A Conserved Role for Snail as a Potentiator of Active Transcription

Genes Dev. 2014 Jan 15;28(2):167-81. doi: 10.1101/gad.230953.113. Epub 2014 Jan 8.

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: Drosophila embryogenesis; Snail; Twist; activation; repression; spatiotemporal gene expression; transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Drosophila / embryology
  • Drosophila / genetics*
  • Drosophila / metabolism*
  • Drosophila Proteins / metabolism
  • Embryo, Nonmammalian
  • Enhancer Elements, Genetic / genetics
  • Gene Expression Regulation, Developmental
  • Mesoderm / metabolism
  • Protein Binding
  • Snail Family Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Twist-Related Protein 1 / metabolism

Substances

  • Drosophila Proteins
  • Snail Family Transcription Factors
  • Transcription Factors
  • Twi protein, Drosophila
  • Twist-Related Protein 1
  • sna protein, Drosophila