RUNX1 regulates the CD34 gene in haematopoietic stem cells by mediating interactions with a distal regulatory element
RUNX1 regulates the CD34 gene in haematopoietic stem cells by mediating interactions with a distal regulatory element
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DOI：
10.1038/emboj.2011.285
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发表时间：
2011-10-05
期刊：
影响因子：
11.4
通讯作者：
Tenen, Daniel G.
中科院分区：
文献类型：
--
作者：
Levantini, Elena;Lee, Sanghoon;Tenen, Daniel G.
转录因子RUNX1是建立造血基因表达程序所必需的；然而，它如何激活造血干细胞(HSC)基因转录的机制仍然不清楚。在这里，我们通过研究人类CD34基因的调控对RUNX1的功能有了新的见解，CD34基因在HSCs中表达。利用携带人CD34PAC结构的转基因小鼠，我们发现了一个新的下游调控元件(DRE)，它与RUNX1结合，是人CD34在长期(LT)-HSCs中表达所必需的。在携带人CD34启动子-DRE结构的小鼠中条件删除RUNX1会取消人CD34的表达。我们通过在LT-HSCs中的染色体构象捕获分析证明了DRE与人CD34启动子的物理相互作用。RUNX结合位点的定向突变导致这种相互作用的干扰，并降低了人CD34在LT-HSCs中的表达。总体而言，我们的体内数据为RUNX1在调节HSC基因CD34远端和近端元件之间的相互作用提供了新的证据。EMBO期刊(2011)30,4059-4070。DOI：10.1038/Intemj.2011.285；2011年8月26日在线发布
The transcription factor RUNX1 is essential to establish the haematopoietic gene expression programme; however, the mechanism of how it activates transcription of haematopoietic stem cell (HSC) genes is still elusive. Here, we obtained novel insights into RUNX1 function by studying regulation of the human CD34 gene, which is expressed in HSCs. Using transgenic mice carrying human CD34 PAC constructs, we identified a novel downstream regulatory element (DRE), which is bound by RUNX1 and is necessary for human CD34 expression in long-term (LT)-HSCs. Conditional deletion of Runx1 in mice harbouring human CD34 promoter-DRE constructs abrogates human CD34 expression. We demonstrate by chromosome conformation capture assays in LT-HSCs that the DRE physically interacts with the human CD34 promoter. Targeted mutagenesis of RUNX binding sites leads to perturbation of this interaction and decreased human CD34 expression in LT-HSCs. Overall, our in vivo data provide novel evidence about the role of RUNX1 in mediating interactions between distal and proximal elements of the HSC gene CD34. The EMBO Journal (2011) 30, 4059-4070. doi:10.1038/emboj.2011.285; Published online 26 August 2011