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

Nat Commun. 2016 Jan 8;7:10160. doi: 10.1038/ncomms10160.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism*
  • Capillaries / metabolism*
  • Chromatin Immunoprecipitation
  • DNA Methylation*
  • Endothelial Cells / metabolism*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Mice
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Mosaicism*
  • NIH 3T3 Cells
  • Phenotype
  • Promoter Regions, Genetic
  • Pulmonary Artery / cytology
  • RNA, Messenger / metabolism*
  • Real-Time Polymerase Chain Reaction
  • von Willebrand Factor / genetics*
  • von Willebrand Factor / metabolism

Substances

  • RNA, Messenger
  • von Willebrand Factor