A Gata2 intronic enhancer confers its pan-endothelia-specific regulation
A Gata2 intronic enhancer confers its pan-endothelia-specific regulation
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DOI：
10.1242/dev.001297
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发表时间：
2007-05-01
期刊：
影响因子：
4.6
通讯作者：
Engel, James Douglas
中科院分区：
文献类型：
--
作者：
Khandekar, Melin;Brandt, William;Engel, James Douglas
GATA-2 是一种转录因子，已被证明在胚胎发生过程中的多个器官系统中发挥重要作用，被认为具有调节多种内皮特异性基因表达的特性。然而，内皮细胞中控制 Gata2 激活的转录调控体系尚未得到充分探索。在这里，我们通过跟踪 Gata2-GFP 敲入胚胎中的 GFP 表达来记录胚胎发生过程中的 GATA-2 内皮表达。通过创始人转基因分析，我们在第四个内含子中鉴定出了 Gata2 内皮增强子，并发现该增强子对 Gata2 的调节仅限于心内膜、淋巴管和血管内皮。增强子内三个 ETS 结合基序的破坏会减弱其活性，而单个 E 盒的消除则会消除转基因小鼠中内皮增强子定向的表达。已知内皮细胞的发育需要 SCL (TAL1)，而 SCL-E12 (SCL-Tcfe2a) 异二聚体可以在体外结合增强子中的关键 E 盒。因此，GATA-2在淋巴管、心脏和血管内皮细胞中早期表达，并且Gata2的全内皮特异性表达由离散的内含子增强子控制。
GATA-2, a transcription factor that has been shown to play important roles in multiple organ systems during embryogenesis, has been ascribed the property of regulating the expression of numerous endothelium-specific genes. However, the transcriptional regulatory hierarchy governing Gata2 activation in endothelial cells has not been fully explored. Here, we document GATA-2 endothelial expression during embryogenesis by following GFP expression in Gata2-GFP knock- in embryos. Using founder transgenic analyses, we identified a Gata2 endothelium enhancer in the fourth intron and found that Gata2 regulation by this enhancer is restricted to the endocardial, lymphatic and vascular endothelium. Whereas disruption of three ETS-binding motifs within the enhancer diminished its activity, the ablation of its single E box extinguished endothelial enhancer-directed expression in transgenic mice. Development of the endothelium is known to require SCL (TAL1), and an SCL-E12 (SCL-Tcfe2a) heterodimer can bind the crucial E box in the enhancer in vitro. Thus, GATA-2 is expressed early in lymphatic, cardiac and blood vascular endothelial cells, and the pan-endothelium-specific expression of Gata2 is controlled by a discrete intronic enhancer.