染色质重塑酶 BRG1 通过两种水平调节血管 Wnt 信号通路。
The chromatin-remodeling enzyme BRG1 modulates vascular Wnt signaling at two levels.
机构信息
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
出版信息
Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2282-7. doi: 10.1073/pnas.1013751108. Epub 2011 Jan 24.
Abstract
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 β-catenin, and an overall decrease in Wnt signaling in endothelial cells. Pharmacological stabilization of β-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.
摘要
ATP 依赖的染色质重塑酶 brahma 相关基因 1（BRG1）在胚胎和出生后发育过程中调节特定靶基因的转录。从胚胎血管中缺失 Brg1 会导致卵黄囊血管重塑缺陷。我们现在报告说，经典 Wnt 信号通路的失调是 Brg1 突变血管表型的基础。Brg1 缺失导致 frizzled 家族的几个 Wnt 受体下调，细胞内 Wnt 信号分子 β-连环蛋白降解，以及内皮细胞中 Wnt 信号的整体减少。β-连环蛋白的药理学稳定显著挽救了 Brg1 突变血管的形态和 Wnt 靶基因的转录。我们的数据表明，BRG1 在血管内皮细胞中通过两种不同的水平影响经典 Wnt 通路：通过 Wnt 受体基因和 Wnt 靶基因的转录调控。这些发现为胚胎血管发育过程中 Wnt 信号的调节建立了一种表观遗传机制。
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