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

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.

SUBMITTER: Yuan L

PROVIDER: S-EPMC5154372 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Yuan Lei L Chan Gary C GC Beeler David D Janes Lauren L Spokes Katherine C KC Dharaneeswaran Harita H Mojiri Anahita A Adams William J WJ Sciuto Tracey T Garcia-Cardeña Guillermo G Molema Grietje G Kang Peter M PM Jahroudi Nadia N Marsden Philip A PA Dvorak Ann A Regan Erzsébet Ravasz ER Aird William C WC

Nature communications 20160108

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 th ...[more]

PMID: 26744078

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Project description:Feed-forward loops (FFLs) are among the most ubiquitously found motifs of reaction networks in nature. However, little is known about their stochastic behavior and the variety of network phenotypes they can exhibit. In this study, we provide full characterizations of the properties of stochastic multimodality of FFLs, and how switching between different network phenotypes are controlled. We have computed the exact steady-state probability landscapes of all eight types of coherent and incoherent FFLs using the finite-butter Accurate Chemical Master Equation (ACME) algorithm, and quantified the exact topological features of their high-dimensional probability landscapes using persistent homology. Through analysis of the degree of multimodality for each of a set of 10,812 probability landscapes, where each landscape resides over 105-106 microstates, we have constructed comprehensive phase diagrams of all relevant behavior of FFL multimodality over broad ranges of input and regulation intensities, as well as different regimes of promoter binding dynamics. In addition, we have quantified the topological sensitivity of the multimodality of the landscapes to regulation intensities. Our results show that with slow binding and unbinding dynamics of transcription factor to promoter, FFLs exhibit strong stochastic behavior that is very different from what would be inferred from deterministic models. In addition, input intensity play major roles in the phenotypes of FFLs: At weak input intensity, FFL exhibit monomodality, but strong input intensity may result in up to 6 stable phenotypes. Furthermore, we found that gene duplication can enlarge stable regions of specific multimodalities and enrich the phenotypic diversity of FFL networks, providing means for cells toward better adaptation to changing environment. Our results are directly applicable to analysis of behavior of FFLs in biological processes such as stem cell differentiation and for design of synthetic networks when certain phenotypic behavior is desired.

Dataset Information

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

Publications

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

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