A role of stochastic phenotype switching in generating mosaic endothelial cell heterogeneity

Lei Yuan, Gary C. Chan, David Beeler, Lauren Janes, Katherine C. Spokes, Harita Dharaneeswaran, Anahita Mojiri, William J. Adams, Tracey Sciuto, Guillermo Garcia-Cardeña, Grietje Molema, Peter M. Kang, Nadia Jahroudi, Philip A. Marsden, Ann Dvorak, Erzsébet Ravasz Regan, William C. Aird

Research output: Contribution to journalArticle

45 Scopus citations

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.

Original languageEnglish (US)
Article number10160
JournalNature Communications
Volume7
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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