The Chromatin-Remodeling Enzymes BRG1 and CHD4 Antagonistically Regulate Vascular Wnt Signaling

Abstract

Canonical Wnt signaling plays an important role in embryonic and postnatal blood vessel development. We previously reported that the chromatin-remodeling enzyme BRG1 promotes vascular Wnt signaling. Vascular deletion of Brg1 results in aberrant yolk sac blood vessel morphology, which is rescued by pharmacological stimulation of Wnt signaling with lithium chloride (LiCl). We have now generated embryos lacking the chromatin-remodeling enzyme Chd4 in vascular endothelial cells. Unlike Brg1 mutants, Chd4 mutant embryos had normal yolk sac vascular morphology. However, concomitant deletion of Chd4 and Brg1 rescued vascular abnormalities seen in Brg1 mutant yolk sacs to the same extent as LiCl treatment. We hypothesized that Wnt signaling was upregulated in Chd4 mutant yolk sac vasculature. Indeed, we found that Chd4 deletion resulted in upregulation of the Wnt-responsive transcription factor Tcf7 and an increase in Wnt target gene expression in endothelial cells. Furthermore, we identified one Wnt target gene, Pitx2, that was downregulated in Brg1 mutant endothelial cells but was rescued following LiCl treatment and in Brg1 Chd4 double mutant vasculature, suggesting that PITX2 helps to mediate the restoration of yolk sac vascular remodeling under both conditions. We conclude that BRG1 and CHD4 antagonistically modulate Wnt signaling in developing yolk sac vessels to mediate normal vascular remodeling.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.06222-11.

ACKNOWLEDGMENTS

We thank Katia Georgopoulos (Harvard Medical School) for Chd4-floxed mice, Vijay Muthukumar and James Riddle for their assistance with mouse husbandry and genotyping, and Rodger McEver and members of the Griffin lab for helpful discussions and critical reading of the manuscript.

This work was supported by National Institutes of Health grants to C.T.G. (R00HL087621 and P20RR018758).