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

被引：75

作者：

Yuan, Lei ^{[1
,2
]}

Chan, Gary C. ^{[1
,2
]}

Beeler, David ^{[1
,2
]}

Janes, Lauren ^{[1
,2
]}

Spokes, Katherine C. ^{[1
,2
]}

Dharaneeswaran, Harita ^{[1
,2
]}

Mojiri, Anahita ^{[3
]}

Adams, William J. ^{[4
]}

Sciuto, Tracey ^{[1
,4
]}

Garcia-Cardena, Guillermo ^{[5
]}

Molema, Grietje ^{[6
]}

Kang, Peter M. ^{[2
,7
]}

Jahroudi, Nadia ^{[3
]}

Marsden, Philip A. ^{[8
,9
]}

Dvorak, Ann ^{[1
,4
]}

Regan, Erzsebet Ravasz ^{[1
,2
,10
]}

Aird, William C. ^{[1
,2
]}

机构：

[1] Beth Israel Deaconess Med Ctr, Dept Med, Vasc Biol Res Ctr, Boston, MA 02215 USA

[2] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA

[3] Univ Alberta, Dept Med, Edmonton, AB T6G 2R3, Canada

[4] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA

[5] Brigham & Womens Hosp, Dept Pathol, Ctr Excellence Vasc Biol, 75 Francis St, Boston, MA 02115 USA

[6] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Med Biol Sect, NL-9700 AB Groningen, Netherlands

[7] Beth Israel Deaconess Med Ctr, Dept Med, Cardiovasc Inst, Boston, MA 02215 USA

[8] Univ Toronto, Dept Med, Toronto, ON M5G 2C4, Canada

[9] St Michaelss Hosp, Toronto, ON M5B 1W8, Canada

[10] Coll Wooster, Biochem & Mol Biol, Wooster, OH 44691 USA

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

美国国家卫生研究院;

关键词：

VON-WILLEBRAND-FACTOR; HAIRPIN-BISULFITE PCR; GENE-EXPRESSION; DNA METHYLATION; NOISE; INHERITANCE; PATTERNS; PROTEIN; ANGIOGENESIS; LANDSCAPE;

D O I：

10.1038/ncomms10160

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：16

共 65 条

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