Notch signaling and Sry-box (Sox) family transcriptional factors both play critical roles in endothelial cell (EC) differentiation in vascularization. Recent studies have shown that excessive Notch signaling induces Sox2 to cause cerebral arteriovenous malformations (AVMs). Here, we examine human pulmonary AVMs and find no induction of Sox2. Results of epigenetic studies also show less alteration of Sox2-DNA binding in pulmonary AVMs than in cerebral AVMs. We identify high expression of ski-interacting protein (Skip) in brain ECs, a Notch-associated chromatin-modifying protein that is lacking in lung ECs. Knockdown of Skip abolished Notch-induction of Sox2 in brain ECs, while restoration of Skip in lung ECs enabled Notch-mediated Sox2 induction. The results suggest that Skip is a key factor for induction of Sox2 in cerebral AVMs.

中文翻译：

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跳过对于Notch信号在脑动静脉畸形中诱导Sox2至关重要。

Notch信号和Sry-box（Sox）家族转录因子均在血管化过程中的内皮细胞（EC）分化中起关键作用。最近的研究表明，过量的Notch信号传导会诱导Sox2引起脑动静脉畸形（AVM）。在这里，我们检查了人肺AVM，没有发现Sox2的诱导。表观遗传学研究的结果还表明，与大脑AVM相比，肺AVM中Sox2-DNA结合的改变更少。我们确定高表达的滑雪互动蛋白（Skip）在脑ECs，缺席相关的染色质修饰蛋白在肺ECs中缺乏。跳过的击倒消除了脑EC中Sox2的Notch诱导，而恢复肺EC中的Skip使得Notch介导的Sox2诱导成为可能。结果表明，跳过是在大脑AVM中诱导Sox2的关键因素。