ETS factors are required but not sufficient for specific patterns of enhancer activity in different endothelial subtypes.
ETS factors are required but not sufficient for specific patterns of enhancer activity in different endothelial subtypes.
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DOI：
10.1016/j.ydbio.2021.01.002
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发表时间：
2021-05
影响因子：
2.7
通讯作者：
De Val S
中科院分区：
文献类型：
--
作者：
Neal A;Nornes S;Louphrasitthiphol P;Sacilotto N;Preston MD;Fleisinger L;Payne S;De Val S
正确的血管分化需要不同亚型内皮细胞中不同的基因表达模式。ETS转录因子家族成员对于动脉和血管生成特异性基因调控元件的转录激活至关重要，这导致了它们在VEGFA信号传导直接下游的动脉和血管生成分化中发挥谱系定义作用的假设。然而，另一种解释是，无论表达模式如何，ETS结合增强子和启动子是许多内皮基因激活的一般要求，并由其他因素提供亚型特异性。在这里，我们通过对Ephb4和Coup-TFII （Nr2f2）静脉特异性增强剂的分析，证明ETS因子对静脉、动脉和血管生成特异性增强剂的活性模式同样重要。此外，我们发现这些血管特异性增强剂的ETS因子结合被VEGFA信号富集，类似于在动脉和血管生成增强剂中所看到的。然而，虽然血管和血管生成增强剂在体内可以被VEGFA激活，但Ephb4和Coup-TFII静脉增强剂却不能，这表明VEGFA诱导的动脉和血管生成增强剂活性的特异性是通过非ets转录因子发生的。这些结果支持一个模型，即ETS因子不是不同内皮亚型中特定基因表达模式的主要调节因子。静脉特异性增强子可能包含基本的ETS基序。VEGFA诱导ETS在静脉、动脉和血管生成增强剂的结合增加。VEGFA刺激不能诱导血管特异性增强剂活性。
Correct vascular differentiation requires distinct patterns of gene expression in different subtypes of endothelial cells. Members of the ETS transcription factor family are essential for the transcriptional activation of arterial and angiogenesis-specific gene regulatory elements, leading to the hypothesis that they play lineage-defining roles in arterial and angiogenic differentiation directly downstream of VEGFA signalling. However, an alternative explanation is that ETS binding at enhancers and promoters is a general requirement for activation of many endothelial genes regardless of expression pattern, with subtype-specificity provided by additional factors. Here we use analysis of Ephb4 and Coup-TFII (Nr2f2) vein-specific enhancers to demonstrate that ETS factors are equally essential for vein, arterial and angiogenic-specific enhancer activity patterns. Further, we show that ETS factor binding at these vein-specific enhancers is enriched by VEGFA signalling, similar to that seen at arterial and angiogenic enhancers. However, while arterial and angiogenic enhancers can be activated by VEGFA in vivo, the Ephb4 and Coup-TFII venous enhancers are not, suggesting that the specificity of VEGFA-induced arterial and angiogenic enhancer activity occurs via non-ETS transcription factors. These results support a model in which ETS factors are not the primary regulators of specific patterns of gene expression in different endothelial subtypes. Vein-specific enhancers can contain essential ETS motifs. VEGFA induced an increase in ETS binding at vein, arterial and angiogenic enhancers. VEGFA stimulation cannot induce vein-specific enhancer activity.
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