Abstract 20643: The Role of Sox7 in Cardiovascular Progenitor Cells

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Significant progress has been made identifying the key regulators of cardiac development. Multiple studies have defined mutations in both Nkx2-5 and Gata4 which contribute to congenital heart disease (CHD). Interactions between Nkx2-5 and Gata4 are well established and display cooperative regulation of downstream target genes. However, it is now appreciated that the interaction of many transcription factors and cofactors is required to instruct the complex morphogenetic and molecular events of cardiac development. Gata4 and Sox7 are located at chromosome 8p23.1. Microdeletions and duplications of this region are associated with CHD. Gata4 haploinsufficiency contributes to the phenotype of patients with 8p23.1 syndromes but does not explain the phenotype in its entirety, suggesting involvement of additional genes in this region with Sox7 as a likely candidate gene. We have previously defined the Nkx2-5 regulatory gene networks in the developing mouse heart and have discovered that Sox7 is expressed in Nkx2-5+ cardiac progenitor cells (CPCs). In these studies, we show overexpression of Sox7 during mouse EB differentiation results in a decrease in Pdgfralpha/Flk1 double positive CPCs in day 4 EBs. Transcriptome analysis of Sox7 overexpressing EBs using RNAseq indicates a significant decrease in cardiac genes while endothelial genes are upregulated. Interestingly, deletion of Sox7 in mESCs using Crispr/Cas9 gene editing also results in impaired EB differentiation to cardiac lineages. Further using single cell qRT-PCR, we establish that Sox7 is coexpressed with Gata4 in a subset of the Nkx2.5+ CPCs. In coimmunoprecipitation experiments, Sox7 is capable of binding Gata4 via the Sox7 HMG domain. Further, preliminary studies suggest Sox7 directly interacts with Nkx2-5, as well. Additionally, our analysis indicates Sox7 deficient embryos are nonviable, display delayed development and perturbed cardiovascular morphogenesis and have decreased expression of several key developmental cardiac genes. Our results indicate that Sox7 plays a dose-dependent role in early cardiac development. Further studies will explore how the interaction of Sox7 with Gata4 and Nkx2-5 regulates transcriptional networks that drive normal cardiac morphogenesis.

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