Gata3 targets Runx1 in the embryonic haematopoietic stem cell niche
Gata3 targets Runx1 in the embryonic haematopoietic stem cell niche
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DOI：
10.1002/iub.2184
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发表时间：
2020-01-01
期刊：
影响因子：
4.6
通讯作者：
Ottersbach, Katrin
中科院分区：
文献类型：
--
作者：
Fitch, Simon R.;Kapeni, Chrysa;Ottersbach, Katrin
RUNX1是一种重要的造血转录因子，与多种血液系统恶性肿瘤密切相关。此外，它是发育过程中第一批造血干细胞(HSCs)出现的关键调节因素。转录因子GATA3也与血液病有关，并被证明通过诱导重要的生态位因子的分泌来促进胚胎中HSC的产生。这两种蛋白都在主动脉-性腺-中肾(AGM)区域的几种不同类型的细胞中表达，在那里产生了第一批HSC；然而，这两个关键转录因子之间在胚胎HSC产生的背景下的直接相互作用尚未得到正式证明。在这项目前的研究中，我们检测到RUNX1和GATA3在AGM中罕见的主动脉下间充质细胞中共定位。此外，RUNX1在GATA3(-/-)胚胎中的表达降低，这也表明HSC的出现发生了转变。使用AGM来源的细胞系作为AGM间质微环境的模型，并进行芯片序列和芯片上实验，我们证明了RUNX1和其他关键的生态位因子，是GATA3的直接靶基因。此外，我们还可以在微环境中活跃的特定增强子元件上定位GATA3与RUNX1基因的结合。这些结果揭示了GATA3和RUNX1在支持胚胎HSCs的利基环境中的直接相互作用，并突出了RUNX1在推动造血内皮细胞向HSCs转分化以及在支持这一过程的基质细胞中的双重作用。
Runx1 is an important haematopoietic transcription factor as stressed by its involvement in a number of haematological malignancies. Furthermore, it is a key regulator of the emergence of the first haematopoietic stem cells (HSCs) during development. The transcription factor Gata3 has also been linked to haematological disease and was shown to promote HSC production in the embryo by inducing the secretion of important niche factors. Both proteins are expressed in several different cell types within the aorta-gonads-mesonephros (AGM) region, in which the first HSCs are generated; however, a direct interaction between these two key transcription factors in the context of embryonic HSC production has not formally been demonstrated. In this current study, we have detected co-localisation of Runx1 and Gata3 in rare sub-aortic mesenchymal cells in the AGM. Furthermore, the expression of Runx1 is reduced in Gata3(-/-) embryos, which also display a shift in HSC emergence. Using an AGM-derived cell line as a model for the stromal microenvironment in the AGM and performing ChIP-Seq and ChIP-on-chip experiments, we demonstrate that Runx1, together with other key niche factors, is a direct target gene of Gata3. In addition, we can pinpoint Gata3 binding to the Runx1 locus at specific enhancer elements which are active in themicroenvironment. These results reveal a direct interaction between Gata3 and Runx1 in the niche that supports embryonic HSCs and highlight a dual role for Runx1 in driving the transdifferentiation of haemogenic endothelial cells into HSCs as well as in the stromal cells that support this process.