Abstract
Previous studies have shown that biological noise may drive dynamic phenotypic mosaicism in isogenic unicellular organisms. However, there is no evidence for a similar mechanism operating in metazoans. Here we show that the endothelial-restricted gene, von Willebrand factor (VWF), is expressed in a mosaic pattern in the capillaries of many vascular beds and in the aorta. In capillaries, the mosaicism is dynamically regulated, with VWF switching between ON and OFF states during the lifetime of the animal. Clonal analysis of cultured endothelial cells reveals that dynamic mosaic heterogeneity is controlled by a low-barrier, noise-sensitive bistable switch that involves random transitions in the DNA methylation status of the VWF promoter. Finally, the hearts of VWF-null mice demonstrate an abnormal endothelial phenotype as well as cardiac dysfunction. Together, these findings suggest a novel stochastic phenotype switching strategy for adaptive homoeostasis in the adult vasculature.
Highlights
Previous studies have shown that biological noise may drive dynamic phenotypic mosaicism in isogenic unicellular organisms
Using in vitro cell culture, we demonstrate that dynamic von Willebrand factor (VWF) mosaicism is generated by the ON/OFF toggle of a low-barrier, noise-sensitive bistable switch, and that it involves random transitions in VWF promoter DNA methylation
Previous studies have shown that VWF expression in the endothelium is higher in veins compared with arteries and in large vessels compared with capillaries[37,38]
Summary
Previous studies have shown that biological noise may drive dynamic phenotypic mosaicism in isogenic unicellular organisms. Clonal analysis of cultured endothelial cells reveals that dynamic mosaic heterogeneity is controlled by a low-barrier, noise-sensitive bistable switch that involves random transitions in the DNA methylation status of the VWF promoter. The hearts of VWF-null mice demonstrate an abnormal endothelial phenotype as well as cardiac dysfunction Together, these findings suggest a novel stochastic phenotype switching strategy for adaptive homoeostasis in the adult vasculature. Using in vitro cell culture, we demonstrate that dynamic VWF mosaicism is generated by the ON/OFF toggle of a low-barrier, noise-sensitive bistable switch, and that it involves random transitions in VWF promoter DNA methylation. We present data that supports a role for mosaicism in endothelial health These findings suggest that biological noise is exploited by selected vascular beds to generate adaptive neighborhood-level phenotypic diversity, providing new insights into mechanisms of endothelial cell heterogeneity
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