Unraveling a novel transcription factor code determining the human arterial-specific endothelial cell signature
Unraveling a novel transcription factor code determining the human arterial-specific endothelial cell signature
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DOI：
10.1182/blood-2013-02-483255
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发表时间：
2013-12-05
期刊：
影响因子：
20.3
通讯作者：
Luttun, Aernout
中科院分区：
文献类型：
--
作者：
Aranguren, Xabier L.;Agirre, Xabier;Luttun, Aernout
动脉和静脉的内皮细胞（EC）具有不同的分子/功能特征。潜在的调节机制尚未完全了解。在这里，我们建立了一个特定的指纹的新鲜分离的动脉和静脉内皮细胞从人脐带包含64动脉和12静脉基因，代表不同的功能/途径。在动脉基因中有8个转录因子（TF），包括Notch靶标HEY 2，目前动脉EC（aEC）特异性的“金标准”决定因素。文化废除差异基因表达的部分原因是逐渐丧失典型的Notch活性和HEY 2表达。值得注意的是，在培养的EC中恢复HEY 2表达或Delta样4诱导的Notch信号传导仅部分恢复了aEC基因特征，而8种TF的组合过表达更稳健地恢复了该指纹。虽然一些TF刺激了少数基因，但其他TF促进了大部分动脉基因。虽然有一些重叠和交叉调节，TF在很大程度上相互补充，在调节aEC基因谱。最后，8个TF在人脐静脉EC中的过表达传达了它们在体内植入Matrigel塞后的动脉样行为。因此，我们的研究表明，Notch信号仅决定了部分的aEC签名，并确定了其他新的和互补的转录球员在复杂的调节人类动静脉EC身份。（血。2013;122（24）：3982-3992）
Endothelial cells (ECs) lining arteries and veins have distinct molecular/functional signatures. The underlying regulatory mechanisms are incompletely understood. Here, we established a specific fingerprint of freshly isolated arterial and venous ECs from human umbilical cord comprising 64 arterial and 12 venous genes, representing distinct functions/pathways. Among the arterial genes were 8 transcription factors (TFs), including Notch target HEY2, the current "gold standard" determinant for arterial EC (aEC) specification. Culture abrogated differential gene expression in part due to gradual loss of canonical Notch activity and HEY2 expression. Notably, restoring HEY2 expression or Delta-like4-induced Notch signaling in cultured ECs only partially reinstated the aEC gene signature, whereas combined overexpression of the 8 TFs restored this fingerprint more robustly. Whereas some TFs stimulated few genes, others boosted a large proportion of arterial genes. Although there was some overlap and crossregulation, the TFs largely complemented each other in regulating the aEC gene profile. Finally, overexpression of the 8 TFs in human umbilical vein ECs conveyed an arterial-like behavior upon their implantation in a Matrigel plug in vivo. Thus, our study shows that Notch signaling determines only part of the aEC signature and identifies additional novel and complementary transcriptional players in the complex regulation of human arteriovenous EC identity. (Blood. 2013;122(24):3982-3992)