PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis
PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis
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DOI：
10.1038/ng.2007.7
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发表时间：
2008-01-01
期刊：
影响因子：
30.8
通讯作者：
Tenen, Daniel G.
中科院分区：
文献类型：
--
作者：
Huang, Gang;Zhang, Pu;Tenen, Daniel G.
ets家族转录因子PU.1（也称为SFPI1）和CBF转录因子家族的dna结合亚基AML1（也称为RUNX1）对于所有造血谱系的产生都是至关重要的，并且两者都在白血病中起肿瘤抑制作用。PU.1的上游调控元件（URE）具有增强和抑制活性，严格调控PU.1的表达。本研究表明，AML1结合到PU.1上游调控元件的重要功能位点，并在胚胎和成年发育阶段调控PU.1的表达。对携带条件AML1敲除等位基因的小鼠和携带URE近端所有三个AML1位点突变的敲入小鼠的分析表明，AML1以谱系依赖的方式正向和负向调节PU.1。在这些小鼠中，PU.1表达的失调导致了观察到的每一种表型，而恢复适当的PU.1表达可以挽救或部分挽救每种表型。因此，我们的数据表明PU.1是AML1的主要下游靶基因。
Both PU.1 (also called SFPI1), an Ets-family transcription factor, and AML1 (also called RUNX1), a DNA-binding subunit of the CBF transcription factor family, are crucial for the generation of all hematopoietic lineages, and both act as tumor suppressors in leukemia. An upstream regulatory element (URE) of PU.1 has both enhancer and repressor activity and tightly regulates PU.1 expression. Here we show that AML1 binds to functionally important sites within the PU.1 upstream regulatory element and regulates PU.1 expression at both embryonic and adult stages of development. Analysis of mice carrying conditional AML1 knockout alleles and knock-in mice carrying mutations in all three AML1 sites of the URE proximal region demonstrated that AML1 regulates PU.1 both positively and negatively in a lineage dependent manner. Dysregulation of PU.1 expression contributed to each of the phenotypes observed in these mice, and restoration of proper PU.1 expression rescued or partially rescued each phenotype. Thus, our data demonstrate that PU.1 is a major downstream target gene of AML1.