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.
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Chan
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: David
authors.initials: D
authors.lastname: Beeler
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Janes
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Spokes
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Harita
authors.initials: H
authors.lastname: Dharaneeswaran
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2R3, Canada.
authors.forename: Anahita
authors.initials: A
authors.lastname: Mojiri
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Adams
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Tracey
authors.initials: T
authors.lastname: Sciuto
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Cardeña
authors.affiliation: Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, 9700 AB Groningen, The Netherlands.
authors.forename: Grietje
authors.initials: G
authors.lastname: Molema
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|Cardiovascular Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kang
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2R3, Canada.
authors.forename: Nadia
authors.initials: N
authors.lastname: Jahroudi
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario M5G 2C4, Canada.|St. Michaels's Hospital, Toronto, Ontario M5B 1W8, Canada.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Marsden
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Dvorak
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Erzsébet Ravasz
authors.initials: ER
authors.lastname: Regan
authors.affiliation: Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Aird
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009030:Mosaicism; D041681:NIH 3T3 Cells; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011651:Pulmonary Artery / Q000166:cytology; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D014841:von Willebrand Factor