Induction of hematopoietic and endothelial cell program orchestrated by ETS transcription factor ER71/ETV2
Induction of hematopoietic and endothelial cell program orchestrated by ETS transcription factor ER71/ETV2
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DOI：
10.15252/embr.201439939
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发表时间：
2015-05-01
期刊：
影响因子：
7.7
通讯作者：
Choi, Kyunghee
中科院分区：
文献类型：
--
作者：
Liu, Fang;Li, Daofeng;Choi, Kyunghee
ETS 因子 ETV2（又名 ER71）对于血液和血管系统的生成至关重要，因为 ETV2 缺陷会导致小鼠血液和内皮细胞形成完全受阻以及胚胎致死。然而，人们对 ETV2 介导的基因调控网络以及控制造血和内皮细胞发育的信号知之甚少。在这里，我们绘制了 ETV2 全局结合位点，并进行了胚胎干细胞的体外分化，以及生殖系和条件敲除小鼠研究，以揭示中胚层血管生成命运承诺所涉及的机制。我们证明 ETV2 与特定造血细胞和内皮细胞谱系的增强子结合。我们发现发育中胚胎中的血管生成祖细胞群可以被鉴定为FLK1（高）PDGFR（-）。值得注意的是，这些血管生成祖细胞对 ETV2 依赖性 FLK1 信号传导完全敏感。重要的是，ETV2 打开其他 Ets 基因，从而建立 ETS 层次结构。因此，由 ETV2 启动的造血和内皮细胞程序部分由其他 ETS 因子通过 ETS 转换机制维持。这些发现强调了瞬时 ETV2 表达在造血和内皮细胞谱系规范和稳定性调节中发挥的关键作用。
The ETS factor ETV2 (aka ER71) is essential for the generation of the blood and vascular system, as ETV2 deficiency leads to a complete block in blood and endothelial cell formation and embryonic lethality in the mouse. However, the ETV2-mediated gene regulatory network and signaling governing hematopoietic and endothelial cell development are poorly understood. Here, we map ETV2 global binding sites and carry out in vitro differentiation of embryonic stem cells, and germ line and conditional knockout mouse studies to uncover mechanisms involved in the hemangiogenic fate commitment from mesoderm. We show that ETV2 binds to enhancers that specify hematopoietic and endothelial cell lineages. We find that the hemangiogenic progenitor population in the developing embryo can be identified as FLK1(high)PDGFR(-). Notably, these hemangiogenic progenitors are exclusively sensitive to ETV2-dependent FLK1 signaling. Importantly, ETV2 turns on other Ets genes, thereby establishing an ETS hierarchy. Consequently, the hematopoietic and endothelial cell program initiated by ETV2 is maintained partly by other ETS factors through an ETS switching mechanism. These findings highlight the critical role that transient ETV2 expression plays in the regulation of hematopoietic and endothelial cell lineage specification and stability.