SOX10 directly modulates ERBB3 transcription via an intronic neural crest enhancer

Abstract

BackgroundThe ERBB3 gene is essential for the proper development of the neural crest (NC) and its derivative populations such as Schwann cells. As with all cell fate decisions, transcriptional regulatory control plays a significant role in the progressive restriction and specification of NC derived lineages during development. However, little is known about the sequences mediating transcriptional regulation of ERBB3 or the factors that bind them.ResultsIn this study we identified three transcriptional enhancers at the ERBB3 locus and evaluated their regulatory potential in vitro in NC-derived cell types and in vivo in transgenic zebrafish. One enhancer, termed ERBB3_MCS6, which lies within the first intron of ERBB3, directs the highest reporter expression in vitro and also demonstrates epigenetic marks consistent with enhancer activity. We identify a consensus SOX10 binding site within ERBB3_MCS6 and demonstrate, in vitro, its necessity and sufficiency for the activity of this enhancer. Additionally, we demonstrate that transcription from the endogenous Erbb3 locus is dependent on Sox10. Further we demonstrate in vitro that Sox10 physically interacts with that ERBB3_MCS6. Consistent with its in vitro activity, we also show that ERBB3_MCS6 drives reporter expression in NC cells and a subset of its derivative lineages in vivo in zebrafish in a manner consistent with erbb3b expression. We also demonstrate, using morpholino analysis, that Sox10 is necessary for ERBB3_MCS6 expression in vivo in zebrafish.ConclusionsTaken collectively, our data suggest that ERBB3 may be directly regulated by SOX10, and that this control may in part be facilitated by ERBB3_MCS6.

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“…Often, intronic regions contain enhancer elements that can greatly influence transcription (4, 25, 26). In addition, the only apparent FOXD3 consensus site in either FOXD3-enriched TWIST1 region was located in intron 1.…”

Establishing neural crest identity: a gene regulatory recipe

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Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3

“…ChIP-seq analysis showed that the first intron of ERBB3 was enriched by FOXD3. This region is well conserved between species and functions as an enhancer region for ERBB3 (30)(31)(32). Quantitative PCR (qPCR) showed dramatic enrichment of intron 1 over normal IgG only following FOXD3 expression ( Figure 2B).…”