Mapping the transcriptional and epigenetic landscape of organotypic endothelial diversity in the developing and adult mouse.

The vascular endothelium features unique molecular and functional properties across different vessel types, such as between arteries, veins and capillaries, as well as between different organs, such as the leaky sinusoidal endothelium of the liver versus the impermeable vessels of the brain. However, the transcriptional networks governing endothelial organ specialization remain unclear. Here we profile the accessible chromatin and transcriptional landscapes of the endothelium from the mouse liver, lung, heart, kidney, brain and retina, across developmental time, to identify potential transcriptional regulators of endothelial heterogeneity. We then determine which of these putative regulators are conserved in human brain endothelial cells, and using single-cell transcriptomic profiling, we define which regulatory networks are active during brain maturation. Finally, we show that the putative transcriptional regulators identified by these three approaches molecularly and functionally reprogram naive endothelial cells. Thus, this resource can be used to identify potential transcriptional regulators controlling the establishment and maintenance of organ-specific endothelial specialization.