ETV2 (Ets Variant Transcription Factor 2)- Cascade Regulates Endothelial Progenitor Cell Migration During Embryogenesis.

OBJECTIVE

Endothelial progenitors migrate early during embryogenesis to form the primary vascular plexus. The regulatory mechanisms that govern their migration are not completely defined. Here, we describe a novel role for ETV2 (Ets variant transcription factor 2) in cell migration and provide evidence for an ETV2 network as a mechanism responsible for this process. Approach and Results: Analysis of RNAseq datasets showed robust enrichment of migratory/motility pathways following overexpression of ETV2 during mesodermal differentiation. We then analyzed ETV2 chromatin immunoprecipitation-seq and assay for transposase accessible chromatin-seq datasets, which showed enrichment of chromatin immunoprecipitation-seq peaks with increased chromatin accessibility in migratory genes following overexpression of ETV2. Migratory assays showed that overexpression of ETV2 enhanced cell migration in mouse embryonic stem cells, embryoid bodies, and mouse embryonic fibroblasts. Knockout of led to migratory defects of angioblasts to their predefined regions of developing embryos relative to wild-type controls at embryonic day (E) 8.5, supporting its role during migration. Mechanistically, we showed that ETV2 binds the promoter region of serving as an upstream regulator of cell migration. Single-cell RNAseq analysis of sorted cells revealed coexpression of and in endothelial progenitors at E7.75 and E8.25. Overexpression of ETV2 led to a robust increase in in both embryoid bodies and mouse embryonic fibroblasts, whereas, its expression was abolished in the knockout embryoid bodies. Finally, shRNA-mediated knockdown of resulted in migration defects, which were partially rescued by overexpression of ETV2.

CONCLUSIONS

These results define an ETV2 cascade, which is important for the regulation of endothelial progenitor cell migration.