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A 3' Enhancer Controls Snail Expression in Melanoma Cells

¹ Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, and ² Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Science, Research Triangle Park, North Carolina

Requests for reprints: Jeremy M. Boss, Rm. 3131, Department of Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322. Phone: 404-727-5973; Fax: 404-727-1719; E-mail: boss{at}microbio.emory.edu and Paul A. Wade, Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Science, Research Triangle Park, NC 27709. Phone: 919-541-3392; Fax: 919-541-0146; E-mail: wadep2{at}niehs.nih.gov.

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 Lys⁴ 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 Lys⁴ dimethylation and H3 acetylation at both the enhancer and the promoter. Additionally, enhancer activity is associated with H3 Lys⁴ 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. [Cancer Res 2007;67(13):6113–20]

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