The tyrosinase enhancer is activated by Sox10 and Mitf in mouse melanocytes

Abstract

The terminal differentiation of melanocytes is associated with the transcriptional activation of genes responsible for pigment production such as tyrosinase. Pigment cell-specific transcription factors, such as Mitf, as well as specific proximal and distal regulatory elements (DRE) are implicated in the tight control of tyrosinase expression during development and adulthood. Proper tyrosinase expression in melanocytes depends upon the presence of a DRE that is located at -15 kb and provides enhancer activity via a central element termed core-enhancer. In this report, we show that the transcription factors Sox10, Mitf and USF-1 are able to activate the core-enhancer in luciferase reporter assays. Comparative sequence analysis identified evolutionarily motifs resembling Sox10 binding sites that were required for full enhancer activity in melanoma cells and in tyrosinase::lacZ transgenic mice. Sox10 was able to bind the DRE in vitro and mutation of the conserved motifs abolished the enhancer transactivation mediated by Sox10. In addition, two highly conserved CAGCTG E-box motifs were identified that were also required for enhancer activity and for transactivation by Mitf. The results suggest that Sox10 directly, and Mitf, most likely indirectly, activate the tyrosinase enhancer, underlining the contribution of Sox10 to tyrosinase gene regulation in melanocytes.

Integration of ChIP-seq and machine learning reveals enhancers and a predictive regulatory sequence vocabulary in melanocytes

“…Hereafter we refer to these 2489 loci as ''putative melanocyte enhancers'' (Supplemental Tables S4-S7). These putative melanocyte enhancers include previously reported enhancers at Tyr and Sox10 (Murisier et al 2007;Antonellis et al 2008), as well as novel enhancers at a number of other genes central to melanocyte biology, including Mitf, Tyrp1, Kit, and Mc1r (Supplemental Fig. S2).…”

Establishing neural crest identity: a gene regulatory recipe

“…Sox10 drives melanocyte specification by directly activating Mitf (Lee et al, 2000;Potterf et al, 2000;Verastegui et al, 2000) in mouse and human cell lines. Mitf in turn acts as a driver of terminal differentiation factors, activating several enzymes responsible for melanin synthesis in pigmented cells, such as those encoded by Dct, Tyr and Si (also known as Pmel) in the mouse (Murisier et al, 2007), as well as factors important for melanocyte survival and proliferation. In this context, Sox10 and Mitf operate in a feed-forward circuit.…”

Metamodels and Phylogenetic Replication: A Systematic Approach to the Evolution of Developmental Pathways

“…In particular, different cis-regulatory elements activate Tyrosinase expression in melanocytes and RPE Murisier et al , 2007a. The melanocyte enhancer is co-activated by MITF and Sox10 (Murisier et al 2007b). In addition to Tyrosinase, MITF induces the expression of several downstream components of melanin synthesis, including Tyrp1, Tyrp2, silver, Aim-1, and others (Slominski et al 2004;Steingrimsson et al 2004;Lin and Fisher 2007).…”