A conserved role for Snail as a potentiator of active transcription

• Published in: Genes & development Vol. 28; no. 2; pp. 167 - 181
• Main Authors: Rembold, Martina, Ciglar, Lucia, Yáñez-Cuna, J Omar, Zinzen, Robert P, Girardot, Charles, Jain, Ankit, Welte, Michael A, Stark, Alexander, Leptin, Maria, Furlong, Eileen E M
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 15.01.2014
• Subjects: Amino Acid Motifs; Animals; Drosophila; Drosophila - embryology; Drosophila - genetics; Drosophila - metabolism; Drosophila Proteins - metabolism; Embryo, Nonmammalian; Enhancer Elements, Genetic - genetics; Gene Expression Regulation, Developmental; Mesoderm - metabolism; Protein Binding; Research Paper; Snail Family Transcription Factors; Transcription Factors - genetics; Transcription Factors - metabolism; Twist-Related Protein 1 - metabolism; Twist; transcription factor; spatiotemporal gene expression; repression; Drosophila embryogenesis; Snail; activation
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.230953.113

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.