The snail gene encodes a transcriptional repressor that functions during animal development and in
cancer progression to promote epithelial-mesenchymal transitions. Strict spatial and temporal boundaries of Snail expression in development imply precise transcriptional control, which becomes inappropriately activated in many
cancer subtypes. To gain insight into the molecular mechanism(s) governing transcriptional control of Snail, we analyze
chromatin structural changes associated with Snail transcription in
melanoma cells. Regardless of transcriptional status, the Snail promoter displays three constitutive
DNase hypersensitive sites (HS) and a moderate level of
histone H3 Lys(4) dimethylation. A robust HS is found in the 3' region of A375
melanoma cells, in which Snail is highly expressed, but is absent in cells not expressing Snail. This
element is conserved throughout the mammalian lineage and strongly activates expression of a reporter in A375 and Colo829
melanoma cells, but not in keratinocytes or primary melanocytes. Activity of this enhancer is associated with enrichment of H3 Lys(4) dimethylation and H3 acetylation at both the enhancer and the promoter. Additionally, enhancer activity is associated with H3 Lys(4) trimethylation at the promoter. A physical interaction between the 3' enhancer and promoter was observed in Snail-expressing cells, demonstrating a direct role for the enhancer in Snail expression. These results suggest a model in which the Snail promoter is constitutively packaged in a poised
chromatin structure that can be activated in
melanoma cells by a tissue-specific enhancer, which physically contacts the promoter.