1Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
2Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota.
Stem Cells Dev. 2019 Aug 15;28(16):1089-1103. doi: 10.1089/scd.2019.0040. Epub 2019 Jul 17.
Specification of the mesodermal lineages requires a complex set of morphogenetic events orchestrated by interconnected signaling pathways and gene regulatory networks. The transcription factor has critical functions in differentiation of multiple mesodermal lineages, including cardiac, endothelial, and hematopoietic. Using a doxycycline-inducible mouse embryonic stem cell line, we have previously shown that expression of in cardiovascular progenitor cells promotes expansion of endothelial progenitor cells (EPCs). In this study, we show that the ability of to promote endothelial cell fate occurs at the expense of the cardiac lineage. Using ChIP-Seq coupled with ATAC-Seq we identify downstream target genes of in cardiovascular progenitor cells and by integrating these data with transcriptomic analyses, we define -dependent gene programs specific to cardiac and EPCs. Furthermore, we demonstrate a protein-protein interaction between SOX7 and GATA4 and provide evidence that SOX7 interferes with the transcriptional activity of GATA4 on cardiac genes. In addition, we show that modulates WNT and BMP signaling during cardiovascular differentiation. Our data represent the first genome-wide analysis of function and reveal a critical role for in regulating signaling pathways that affect cardiovascular progenitor cell differentiation.
中胚层谱系的特化需要一系列复杂的形态发生事件来协调，这些事件由相互连接的信号通路和基因调控网络来实现。转录因子在包括心脏、内皮和造血在内的多种中胚层谱系的分化中具有关键功能。我们之前使用一种四环素诱导的小鼠胚胎干细胞系证明，在心血管祖细胞中表达 可促进内皮祖细胞（EPC）的扩增。在这项研究中，我们表明， 促进内皮细胞命运的能力是以牺牲心脏谱系为代价的。我们通过结合 ChIP-Seq 和 ATAC-Seq 鉴定了心血管祖细胞中 的下游靶基因，并通过整合这些数据与转录组分析，我们定义了特定于心脏和 EPC 的 - 依赖性基因程序。此外，我们证明了 SOX7 和 GATA4 之间存在蛋白-蛋白相互作用，并提供了证据表明 SOX7 干扰了 GATA4 在心脏基因上的转录活性。此外，我们还表明， 在心血管分化过程中调节 WNT 和 BMP 信号。我们的数据代表了对 功能的首次全基因组分析，揭示了 在调节影响心血管祖细胞分化的信号通路方面的关键作用。
