TY - JOUR
T1 - A conserved role for Snail as a potentiator of active transcription
AU - Rembold, Martina
AU - Ciglar, Lucia
AU - Yáñez-Cuna, J Omar
AU - Zinzen, Robert P
AU - Girardot, Charles
AU - Jain, Ankit
AU - Welte, Michael A
AU - Stark, Alexander
AU - Leptin, Maria
AU - Furlong, Eileen E M
PY - 2014/1/15
Y1 - 2014/1/15
N2 - 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.
AB - 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.
KW - Amino Acid Motifs
KW - Animals
KW - Drosophila/embryology
KW - Drosophila Proteins/metabolism
KW - Embryo, Nonmammalian
KW - Enhancer Elements, Genetic/genetics
KW - Gene Expression Regulation, Developmental
KW - Mesoderm/metabolism
KW - Protein Binding
KW - Snail Family Transcription Factors
KW - Transcription Factors/genetics
KW - Twist-Related Protein 1/metabolism
U2 - 10.1101/gad.230953.113
DO - 10.1101/gad.230953.113
M3 - Article
C2 - 24402316
SN - 0890-9369
VL - 28
SP - 167
EP - 181
JO - Genes and Development
JF - Genes and Development
IS - 2
ER -