title: A conserved role for Snail as a potentiator of active transcription.
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.
authors.affiliation: Institute of Genetics, University of Cologne, 50674 Cologne, Germany;
authors.forename: Martina
authors.initials: M
authors.lastname: Rembold
authors.forename: Lucia
authors.initials: L
authors.lastname: Ciglar
authors.forename: J Omar
authors.initials: JO
authors.lastname: Yáñez-Cuna
authors.forename: Robert P
authors.initials: RP
authors.lastname: Zinzen
authors.forename: Charles
authors.initials: C
authors.lastname: Girardot
authors.forename: Ankit
authors.initials: A
authors.lastname: Jain
authors.forename: Michael A
authors.initials: MA
authors.lastname: Welte
authors.forename: Alexander
authors.initials: A
authors.lastname: Stark
authors.forename: Maria
authors.initials: M
authors.lastname: Leptin
authors.forename: Eileen E M
authors.initials: EE
authors.lastname: Furlong
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D004330:Drosophila / Q000196:embryology / Q000235:genetics* / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism; D004625:Embryo, Nonmammalian; D004742:Enhancer Elements, Genetic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D008648:Mesoderm / Q000378:metabolism; D011485:Protein Binding; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C497753:Twi protein, Drosophila; D051879:Twist-Related Protein 1; C000604451:sna protein, Drosophila
keywords: Drosophila embryogenesis; Snail; Twist; activation; repression; spatiotemporal gene expression; transcription factor