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

doi:10.1038/ncomms10160

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

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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 language	English (US)
Article number	10160
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10160
State	Published - 2016

ASJC Scopus subject areas

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

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Yuan, L., Chan, G. C., Beeler, D., Janes, L., Spokes, K. C., Dharaneeswaran, H., Mojiri, A., Adams, W. J., Sciuto, T., Garcia-Cardeña, G., Molema, G., Kang, P. M., Jahroudi, N., Marsden, P. A., Dvorak, A., Regan, E. R., & Aird, W. C. (2016). A role of stochastic phenotype switching in generating mosaic endothelial cell heterogeneity. Nature Communications, 7, Article 10160. https://doi.org/10.1038/ncomms10160

Yuan, L, Chan, GC, Beeler, D, Janes, L, Spokes, KC, Dharaneeswaran, H, Mojiri, A, Adams, WJ, Sciuto, T, Garcia-Cardeña, G, Molema, G, Kang, PM, Jahroudi, N, Marsden, PA, Dvorak, A, Regan, ER & Aird, WC 2016, 'A role of stochastic phenotype switching in generating mosaic endothelial cell heterogeneity', Nature Communications, vol. 7, 10160. https://doi.org/10.1038/ncomms10160

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title = "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.",

author = "Lei Yuan and Chan, {Gary C.} and David Beeler and Lauren Janes and Spokes, {Katherine C.} and Harita Dharaneeswaran and Anahita Mojiri and Adams, {William J.} and Tracey Sciuto and Guillermo Garcia-Carde{\~n}a and Grietje Molema and Kang, {Peter M.} and Nadia Jahroudi and Marsden, {Philip A.} and Ann Dvorak and Regan, {Erzs{\'e}bet Ravasz} and Aird, {William C.}",

note = "Funding Information: We are grateful to Jan A.A.M. Kamps and Peter J. Zwiers for their technical help with harvesting liver endothelial cells, to Claudia Prahst for her technical help with b-galactosidase/CD31 co-staining of aorta preparations, to Dan Li and Shou-Ching Jaminet for their technical help with qPCR assays, to Joel Lawitts for generating mice, and to Chandra Gosh and Zolt{\'a}n Toroczkai for their helpful discussions on the broad significance of our work. This work was supported by National Institutes of Health: National Heart, Lung and Blood Institute, grants HL119322 (W.C.A. and E.R.R.) and HL076540-10 (W.C.A., P.M. and G.G.-C.), as well as the American Heart Association: grant 14STG18590001 (L.Y.).",

year = "2016",

doi = "10.1038/ncomms10160",

language = "English (US)",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

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T1 - A role of stochastic phenotype switching in generating mosaic endothelial cell heterogeneity

AU - Yuan, Lei

AU - Chan, Gary C.

AU - Beeler, David

AU - Janes, Lauren

AU - Spokes, Katherine C.

AU - Dharaneeswaran, Harita

AU - Mojiri, Anahita

AU - Adams, William J.

AU - Sciuto, Tracey

AU - Garcia-Cardeña, Guillermo

AU - Molema, Grietje

AU - Kang, Peter M.

AU - Jahroudi, Nadia

AU - Marsden, Philip A.

AU - Dvorak, Ann

AU - Regan, Erzsébet Ravasz

AU - Aird, William C.

N1 - Funding Information: We are grateful to Jan A.A.M. Kamps and Peter J. Zwiers for their technical help with harvesting liver endothelial cells, to Claudia Prahst for her technical help with b-galactosidase/CD31 co-staining of aorta preparations, to Dan Li and Shou-Ching Jaminet for their technical help with qPCR assays, to Joel Lawitts for generating mice, and to Chandra Gosh and Zoltán Toroczkai for their helpful discussions on the broad significance of our work. This work was supported by National Institutes of Health: National Heart, Lung and Blood Institute, grants HL119322 (W.C.A. and E.R.R.) and HL076540-10 (W.C.A., P.M. and G.G.-C.), as well as the American Heart Association: grant 14STG18590001 (L.Y.).

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

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

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