The chromatin-remodeling enzyme BRG1 modulates vascular Wnt signaling at two levels
The chromatin-remodeling enzyme BRG1 modulates vascular Wnt signaling at two levels
复制标题
DOI：
10.1073/pnas.1013751108
复制
发表时间：
2011-02-08
影响因子：
11.1
通讯作者：
Magnuson, Terry
中科院分区：
文献类型：
--
作者：
Griffin, Courtney T.;Curtis, Carol D.;Magnuson, Terry
ATP依赖性染色质重塑酶brahma相关基因1（BRG 1）在胚胎和出生后发育过程中调节特定靶基因的转录。胚胎血管Brg 1缺失导致卵黄囊血管重构缺陷。我们现在报告，经典Wnt信号通路的失调是许多Brg 1突变血管表型的基础。Brg 1缺失导致卷曲家族的几种Wnt受体的下调，细胞内Wnt信号分子β-连环蛋白的降解，以及内皮细胞中Wnt信号的总体减少。β-连环蛋白的药理学稳定显著挽救了Brg 1突变体血管形态和Wnt靶基因的转录。我们的数据表明，BRG 1影响经典Wnt通路在两个不同的水平在血管内皮细胞：通过转录调节Wnt受体基因和Wnt靶基因。这些发现建立了胚胎血管发育过程中Wnt信号调节的表观遗传机制。
The ATP-dependent chromatin-remodeling enzyme brahma-related gene 1 (BRG1) regulates transcription of specific target genes during embryonic and postnatal development. Deletion of Brg1 from embryonic blood vessels results in yolk sac vascular remodeling defects. We now report that misregulation of the canonical Wnt signaling pathway underlies many Brg1 mutant vascular phenotypes. Brg1 deletion resulted in down-regulation of several Wnt receptors of the frizzled family, degradation of the intracellular Wnt signaling molecule beta-catenin, and an overall decrease in Wnt signaling in endothelial cells. Pharmacological stabilization of beta-catenin significantly rescued Brg1 mutant vessel morphology and transcription of Wnt target genes. Our data demonstrate that BRG1 impacts the canonical Wnt pathway at two different levels in vascular endothelium: through transcriptional regulation of both Wnt receptor genes and Wnt target genes. These findings establish an epigenetic mechanism for the modulation of Wnt signaling during embryonic vascular development.