Distinct contributions of Etv2+ and Flk1+ progenitors to endothelial, hematopoietic, and cardiac lineages

The ETS family transcription factor ETV2, VEGFA and its receptor FLK1 are essential for hematopoietic, vascular and cardiac development. Here, we combine dual Etv2 and Flk1 lineage tracing with molecular profiling to define how mesoderm progenitors are allocated to hematopoietic, endothelial, cardiomyocyte and smooth muscle lineages. We demonstrate that hematopoietic, endothelial, and cardiac valves arise from dual Etv2+ and Flk1+ lineages and that Etv2+ and Flk1+ mesoderm contributing to the hemangiogenic fate is molecularly distinct from those generating muscle. Mechanistically, we show that ETV2 cooperates with the BAF chromatin remodeling complex to establish accessibility at ETV2 target loci. Loss of Baf155 expression reduces chromatin accessibility at ETV2 target loci and impairs hemangiogenic lineage specification. This work defines lineage relationships and the molecular circuitry underlying hemangiogenic specification during cardiovascular development. Overall design: ATAC-seq profiling of day 4 embryoid bodies (EBs) derived from wildtype, Etv2 overexpressing and Etv2KO mouse ES cells. Etv2 overexpression was induced by treating day 2.5 EBs with 2ug/ml doxycline. EBs were sorted by FACS to sort PDGFRalpha+FLK1+ (DP) and PDGFRalpha-FLK1+ (SP) mesodermal cells.