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The role of a neural crest developmental transcriptional program, which critically involves Sox10 upregulation, is a key conserved aspect of melanoma initiation in both humans and zebrafish, yet transcriptional regulation of  sox10  expression is incompletely understood. Here we used ATAC-Seq analysis of multiple zebrafish melanoma tumors to identify recurrently open chromatin domains as putative melanoma-specific  sox10  enhancers. Screening in vivo with EGFP reporter constructs revealed 9 of 11 putative  sox10  enhancers with embryonic activity in zebrafish. Focusing on the most active enhancer region in melanoma, we identified a region 23 kilobases upstream of  sox10 , termed  peak5 , that drives  EGFP  reporter expression in a subset of neural crest cells, Kolmer-Agduhr neurons, and early melanoma patches and tumors with high specificity. A ~200 base pair region, conserved in  Cyprinidae , within  peak5  is required for transgenic reporter activity in neural crest and melanoma. This region contains dimeric SoxE/Sox10 dimeric binding sites essential for  peak5  neural crest and melanoma activity. We show that deletion of the endogenous  peak5  conserved genomic locus decreases embryonic  sox10  expression and disrupts adult stripe patterning in our melanoma model background. Our work demonstrates the power of linking developmental and cancer models to better understand neural crest identity in melanoma.

Functional in vivo characterization of sox10 enhancers in neural crest and melanoma development