Nonredundant roles for Runx1 alternative promoters reflect their activity at discrete stages of developmental hematopoiesis
Nonredundant roles for Runx1 alternative promoters reflect their activity at discrete stages of developmental hematopoiesis
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DOI：
10.1182/blood-2009-08-238626
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发表时间：
2010-04-15
期刊：
影响因子：
20.3
通讯作者：
de Bruijn, Marella F. T. R.
中科院分区：
文献类型：
--
作者：
Bee, Thomas;Swiers, Gemma;de Bruijn, Marella F. T. R.
转录因子Runx 1是小鼠个体发育中决定性造血的关键调节因子。脊椎动物Runx 1由2个启动子转录，远端P1和近端P2，这提供了Runx 1功能的复杂转录和翻译控制的范例。然而，很少有人知道替代Runx 1启动子的使用在确定的造血细胞出现的生物学相关性。在这里，我们报告说，这两个启动子是活跃的，在非常明确的造血的发病，向P2倾斜。此外，一种新的P1-null和减毒P2小鼠模型的功能和形态学分析表明，虽然这两个启动子发挥重要的非冗余的作用，在出现永久性造血细胞，近端P2是最关键的需要。观察到的表型的性质是指示的差异贡献的P1和P2启动子控制的整体Runx 1水平，在这里和当这是最关键的需要。此外，P1-Runx 1和P2-Runx 1的动态表达表明在发育早期需要Runx 1，此时P2仍然是新生造血内皮细胞和/或第一定型造血细胞中的普遍启动子。（血。2010;115（15）：3042-3050）
The transcription factor Runx1 is a pivotal regulator of definitive hematopoiesis in mouse ontogeny. Vertebrate Runx1 is transcribed from 2 promoters, the distal P1 and proximal P2, which provide a paradigm of the complex transcriptional and translational control of Runx1 function. However, very little is known about the biologic relevance of alternative Runx1 promoter usage in definitive hematopoietic cell emergence. Here we report that both promoters are active at the very onset of definitive hematopoiesis, with a skewing toward the P2. Moreover, functional and morphologic analysis of a novel P1-null and an attenuated P2 mouse model revealed that although both promoters play important nonredundant roles in the emergence of definitive hematopoietic cells, the proximal P2 was most critically required for this. The nature of the observed phenotypes is indicative of a differential contribution of the P1 and P2 promoters to the control of overall Runx1 levels, where and when this is most critically required. In addition, the dynamic expression of P1-Runx1 and P2-Runx1 points at a requirement for Runx1 early in development, when the P2 is still the prevalent promoter in the emerging hemogenic endothelium and/or first committed hematopoietic cells. (Blood. 2010;115(15):3042-3050)