Distal upstream tyrosinase S/MAR-containing sequence has regulatory properties specific to subsets of melanocytes

A distal upstream regulatory element of the mouse tyrosinase gene has locus control region (LCR)-like activity and is required for position-independent expression of linked genes. It consists of a DNAse I hypersensitive site, which has enhancer activity in neural crest-derived melanocytes, embedded within a scaffold/matrix attachment region (S/MAR), both of which are necessary for LCR activity. To address the role of the S/MAR in position-independent expression, we assessed the ability of a fragment containing most of the S/MAR to insulate a transgene from position effects. The S/MAR sequence showed a striking cell type specificity in its function in all six multicopy transgenic lines, dampening position effects considerably in cutaneous melanocytes while allowing no expression in other neural crest-derived melanocytes, and causing elevated expression in ocular melanocytes derived from the neural tube. The specificity of transgene expression in the eye suggested the presence of both positive and negative regulatory elements in this enhancer/S/MAR region, which was confirmed by transient transfection analyses. This is the first known regulatory element to exhibit different activities in melanocytes of different developmental origins.