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Transcriptional Control of an Arterial Specific Enhancer from the Endothelin Converting Enzyme-1 Locus

  • Author(s): Robinson, Ashley
  • Advisor(s): Black, Brian
  • et al.
Abstract

Proper specification of veins and arteries is crucial for the development of a functional vasculature. The underlying mechanisms controlling vascular subspecification remains an area of intense study, as incorrect arterio-venous (AV) identity can lead to vascular failure and developmental lethality. A substantial body of work has focused on the cell non-autonomous control of AV subspecification, and in particular, the Notch signaling pathway has been shown to be crucial for this process. By contrast, much less is known about the transcription factors and the cell autonomous control of AV subspecification. We have recently discovered a 600 bp enhancer within the Endothelin Converting Enzyme-1 (ECE1) locus with activity that co-localizes in vivo with arterial, but not venous, markers by immunofluorescence. This enhancer was discovered via a genome wide screen for composite FOX:ETS motifs, which are enriched in endothelial-specific enhancers. In addition to the FOX:ETS motif, we identified a well-conserved, putative Sox transcription factor binding site. We have demonstrated that this cis-element is bound by Sox family members in vitro, and is required for enhancer activity in transgenic mice. While recent publications reveal a role for members of the SoxF subfamily (Sox7, Sox17, and Sox18) in vascular development, whether they play a role in mammalian AV sub-specification remains unclear. Our data indicate that of these factors, Sox17 can coordinate with Foxc2 and Etv2, Forkhead and Ets factors that regulate transcription via FOX:ETS binding, to enhance transcriptional activity of the ECE1 enhancer. Furthermore, we provide data supporting a role for Sox17 in AV sub-specification.

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