The transcription factors Ets1 and Sox10 interact during murine melanocyte development

Abstract

Melanocytes, the pigment-producing cells, arise from multipotent neural crest (NC) cells during embryogenesis. Many genes required for melanocyte development were identified using mouse pigmentation mutants. The variable spotting mouse pigmentation mutant arose spontaneously at the Jackson Laboratory. We identified a G-to-A nucleotide transition in exon 3 of the Ets1 gene in variable spotting, which results in a missense G102E mutation. Homozygous variable spotting mice exhibit sporadic white spotting. Similarly, mice carrying a targeted deletion of Ets1 exhibit hypopigmentation; nevertheless, the function of Ets1 in melanocyte development is unknown. The transcription factor Ets1 is widely expressed in developing organs and tissues, including the NC. In the chick, Ets1 is required for the expression of Sox10, a transcription factor critical for the development of various NC derivatives, including melanocytes. We show that Ets1 is required early for murine NC cell and melanocyte precursor survival in vivo. Given the importance of Ets1 for Sox10 expression in the chick, we investigated a potential genetic interaction between these genes by comparing the hypopigmentation phenotypes of single and double heterozygous mice. The incidence of hypopigmentation in double heterozygotes was significantly greater than in single heterozygotes. The area of hypopigmentation in double heterozygotes was significantly larger than would be expected from the addition of the areas of hypopigmentation of single heterozygotes, suggesting that Ets1 and Sox10 interact synergistically in melanocyte development. Since Sox10 is also essential for enteric ganglia development, we examined the distal colons of Ets1 null mutants and found a significant decrease in enteric innervation, which was exacerbated by Sox10 heterozygosity. At the molecular level, Ets1 was found to activate an enhancer critical for Sox10 expression in NC-derived structures. Furthermore, enhancer activation was significantly inhibited by the variable spotting mutation. Together, these results suggest that Ets1 and Sox10 interact to promote proper melanocyte and enteric ganglia development from the NC.

WNT/β-CATENIN modulates the axial identity of ES derived human neural crest

“…Here, in agreement with Frith et al (2018), we found that posterior NCCs express ETS1, previously thought to be restricted to anterior NCCs, and promote chondrocyte differentiation (Sugiura and Ito, 2010). Moreover, ETS1 has been linked to trunk melanocytes (Gao et al, 2010;Saldana-Caboverde et al, 2015;Ye et al, 2010). NC culture conditions for differentiation reveal a wider potential for NCCs in vitro than in in vivo, and thus inductive signals in vitro appear stronger than those present in vivo (Abzhanov et al, 2003;Dupin et al, 2018;McGonnell and Graham, 2002).…”

MEK inhibition remodels the active chromatin landscape and induces SOX10 genomic recruitment in BRAF(V600E) mutant melanoma cells

“…These results for SOX10 in melanocytes correlate with previous data showing other SOX family members can bind to super-enhancers and regulate lineage-specific genes in chondrocytes and hair follicle stem cells [37,38]. Strikingly, the super-enhancer-associated genes bound by SOX10 included MITF, TFAP2A, ETS1, ZEB2, and SNAI2, each lineage-specific transcription factors known to play important roles in melanocyte development and pigmentation [41,66,67,[96][97][98][99][100]. Several of these factors exhibit co-binding and/or regulation of one another during neural crest and melanocyte development; for example, ETS1 and SOX10 interact to promote proper melanocyte development [40,99], TFAP2A and MITF interact to regulate pigmentation [54,100], and SOX10 activates MITF, while MITF has been suggested to have the capacity to both activate and repress SOX10 expression [74-77, 101, 102].…”

“…Strikingly, the super-enhancer-associated genes bound by SOX10 included MITF, TFAP2A, ETS1, ZEB2, and SNAI2, each lineage-specific transcription factors known to play important roles in melanocyte development and pigmentation [41,66,67,[96][97][98][99][100]. Several of these factors exhibit co-binding and/or regulation of one another during neural crest and melanocyte development; for example, ETS1 and SOX10 interact to promote proper melanocyte development [40,99], TFAP2A and MITF interact to regulate pigmentation [54,100], and SOX10 activates MITF, while MITF has been suggested to have the capacity to both activate and repress SOX10 expression [74-77, 101, 102]. SOX10 binding at super-enhancers near these genes suggests SOX10 is integral to the complex regulatory cross talk exhibited by these lineage-determining transcription factors.…”

Bromodomain and extra-terminal domain (BET) proteins regulate melanocyte differentiation

“…We found that BET inhibition suppressed the expression of additional pigmentation genes regulating these melanocyte functions. The mRNA levels of many transcriptional regulators that affect the level of pigmentation, including Sox10 [58], Ets1 [59], and Irf4 [39], were also reduced while the expression of Tfap2 was strongly increased in both Melb-a melanoblasts and SK-MEL-147 melanoma cells. TFAP2, which promotes melanocyte differentiation by activating a subset of MITF target genes, is frequently lost in melanoma due to silencing by CpG methylation [60,61].…”