GATA2 is well recognized as a key transcription factor and regulator of cell‐type specificity and differentiation. Here, we carried out comparative chromatin immunoprecipitation with comprehensive sequencing (ChIP‐seq) to determine genome‐wide occupancy of GATA2 in endothelial cells and erythroids, and compared the occupancy to the respective gene expression profile in each cell type. Although GATA2 was commonly expressed in both cell types, different GATA2 bindings and distinct cell‐specific gene expressions were observed. By using the ChIP‐seq with epigenetic histone modifications and chromatin conformation capture assays; we elucidated the mechanistic regulation of endothelial‐specific GATA2‐mediated endomucin gene expression, that was regulated by the endothelial‐specific chromatin loop with a GATA2‐associated distal enhancer and core promoter. Knockdown of endomucin markedly attenuated endothelial cell growth, migration and tube formation. Moreover, abrogation of GATA2 in endothelium demonstrated not only a reduction of endothelial‐specific markers, but also induction of mesenchymal transition promoting gene expression. Our findings provide new insights into the correlation of endothelial‐expressed GATA2 binding, epigenetic modification, and the determination of endothelial cell specificity.