Lilly Andrew J, Costa Guilherme, Largeot Anne, Fadlullah Muhammad Z H, Lie-A-Ling Michael, Lacaud Georges, Kouskoff Valerie
Stem Cell Hematopoiesis, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Development. 2016 Dec 1;143(23):4341-4351. doi: 10.1242/dev.140970. Epub 2016 Oct 17.
Endothelial to hematopoietic transition (EHT) is a dynamic process involving the shutting down of endothelial gene expression and switching on of hematopoietic gene transcription. Although the factors regulating EHT in hemogenic endothelium (HE) of the dorsal aorta have been relatively well studied, the molecular regulation of yolk sac HE remains poorly understood. Here, we show that SOX7 inhibits the expression of RUNX1 target genes in HE, while having no effect on RUNX1 expression itself. We establish that SOX7 directly interacts with RUNX1 and inhibits its transcriptional activity. Through this interaction we demonstrate that SOX7 hinders RUNX1 DNA binding as well as the interaction between RUNX1 and its co-factor CBFβ. Finally, we show by single-cell expression profiling and immunofluorescence that SOX7 is broadly expressed across the RUNX1 yolk sac HE population compared with SOX17. Collectively, these data demonstrate for the first time how direct protein-protein interactions between endothelial and hematopoietic transcription factors regulate contrasting transcriptional programs during HE differentiation and EHT.
内皮细胞向造血细胞转变（EHT）是一个动态过程，涉及内皮基因表达的关闭和造血基因转录的开启。尽管在背主动脉的造血内皮（HE）中调节EHT的因子已得到较为充分的研究，但卵黄囊HE的分子调控仍知之甚少。在此，我们表明SOX7抑制HE中RUNX1靶基因的表达，而对RUNX1自身的表达没有影响。我们证实SOX7直接与RUNX1相互作用并抑制其转录活性。通过这种相互作用，我们证明SOX7阻碍RUNX1与DNA的结合以及RUNX1与其辅因子CBFβ之间的相互作用。最后，我们通过单细胞表达谱分析和免疫荧光显示，与SOX17相比，SOX7在RUNX1卵黄囊HE群体中广泛表达。这些数据首次共同证明了内皮和造血转录因子之间的直接蛋白质-蛋白质相互作用如何在HE分化和EHT过程中调节相反的转录程序。
