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Cell
2008 Dec 12;1356:1053-64. doi: 10.1016/j.cell.2008.10.049.
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Combinatorial regulation of endothelial gene expression by ets and forkhead transcription factors.
De Val S
,
Chi NC
,
Meadows SM
,
Minovitsky S
,
Anderson JP
,
Harris IS
,
Ehlers ML
,
Agarwal P
,
Visel A
,
Xu SM
,
Pennacchio LA
,
Dubchak I
,
Krieg PA
,
Stainier DY
,
Black BL
.
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Vascular development begins when mesodermal cells differentiate into endothelial cells, which then form primitive vessels. It has been hypothesized that endothelial-specific gene expression may be regulated combinatorially, but the transcriptional mechanisms governing specificity in vascular gene expression remain incompletely understood. Here, we identify a 44 bp transcriptional enhancer that is sufficient to direct expression specifically and exclusively to the developing vascular endothelium. This enhancer is regulated by a composite cis-acting element, the FOX:ETS motif, which is bound and synergistically activated by Forkhead and Ets transcription factors. We demonstrate that coexpression of the Forkhead protein FoxC2 and the Ets protein Etv2 induces ectopic expression of vascular genes in Xenopus embryos, and that combinatorial knockdown of the orthologous genes in zebrafish embryos disrupts vascular development. Finally, we show that FOX:ETS motifs are present in many known endothelial-specific enhancers and that this motif is an efficient predictor of endothelial enhancers in the human genome.
Figure 3. Misexpression of FoxC2 and Etv2 in Xenopus Embryos Induces Ectopic Endothelial Gene ExpressionXenopus embryos were injected with mRNAs encoding FoxC2 and Etv2 or EGFP control mRNA at the 4-cell stage and then collected at stage 36. After collection, embryos were either assayed by in situ hybridization using flk1 probe, followed by sectioning (A and B), or RNA was extracted for qPCR analysis of flk1 (C) or Pecam (D) transcripts. (A and B) flk1 expression was observed in the cardinal veins (CVs) in control (A) and FoxC2 + Etv2-injected (B) embryos. In addition, ectopic expression of flk1 was readily observed in the endoderm of the caudal region of FoxC2 + Etv2-injected embryos (B) but not in EGFP control injected embryos (A).(C and D) Quantitative, real-time PCR shows that neither FoxC2 nor Etv2 significantly activated flk1 or Pecam expression on their own, but the combination of the two factors strongly induced expression of both endothelial-specific markers. Data are shown as the mean relative expression of flk1 or Pecam transcripts for three independent sets of injections and analyses. Error bars indicate the SEM.
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