RUNX1 and the endothelial origin of blood

The transcription factor RUNX1 is required in the embryo for formation of the adult hematopoietic system. Here we describe the seminal findings that led to the discovery of RUNX1 and of its critical role in blood cell formation in the embryo from hemogenic endothelium. We also present RNA-Seq data demonstrating that hemogenic endothelial cells in different anatomic sites, which produce hematopoietic progenitors with dissimilar differentiation potentials, are molecularly distinct. Hemogenic endothelial cells and non-hemogenic endothelial cells in the yolk sac are more closely related to each other than either are to hemogenic or non-hemogenic endothelial cells in the major arteries. Thus, a major driver of the different lineage potentials of the committed erythro-myeloid progenitors that emerge in the yolk sac, versus hematopoietic stem cells that originate in the major arteries, is likely to be the distinct molecular properties of the hemogenic endothelial cells from which they are derived. We use bioinformatics analyses to predict signaling pathways active in arterial hemogenic endothelium, several of which are functionally validated pathways including Notch, Wnt, and Hedgehog. We also use a novel bioinformatics approach to assemble transcriptional regulatory networks and predict transcription factors that may be specifically involved in hematopoietic cell formation from arterial hemogenic endothelium, which is the origin of the adult hematopoietic system. 16 samples were analyzed and each has two replicates.转录因子RUNX1是胚胎发育过程中形成成体造血系统所必需的。本研究详述了推动RUNX1发现的开创性研究成果，以及其在胚胎阶段由生血内皮（hemogenic endothelium）分化形成血细胞过程中的关键作用。本研究同时提供RNA测序（RNA-Seq）数据，证明不同解剖部位的生血内皮细胞在分子层面存在显著差异——这些细胞可产生具有不同分化潜能的造血祖细胞。卵黄囊中的生血内皮细胞与非生血内皮细胞的分子亲缘关系，均比其与大动脉中的生血或非生血内皮细胞的亲缘关系更为紧密。因此，卵黄囊中产生的定型红系-髓系祖细胞与大动脉中起源的造血干细胞二者的谱系潜能存在差异，其核心驱动因素很可能是二者来源的生血内皮细胞所具有的独特分子特性。本研究通过生物信息学分析，预测了大动脉生血内皮细胞中活跃的信号通路，其中Notch、Wnt及Hedgehog等通路均已通过功能实验验证。此外，本研究采用一种新型生物信息学方法，构建了转录调控网络，并预测了可能特异性参与大动脉生血内皮细胞分化为成体造血系统起源的血细胞过程的转录因子。本研究共分析16份样本，每份样本均设有两个生物学重复。