Epigenetic enhancer modifications determine the angiogenic to quiescent endothelial state transition

The transcriptomic changes in endothelial cells during the state transition from the angiogenic to the quiescent phenotype are controlled by extrinsic microenvironmental factors and intrinsic epigenetic determinants. While significant progress has been made in understanding the external factors and their molecular impacts on this transition, the internal, cell-intrinsic mechanisms driving endothelial state transition remain less explored. Here, we present a detailed multiomic analysis of the epigenetic-driven state transition in angiogenic versus homeostatic lung capillary endothelial cells by mapping the histone code, accessible chromatin, and DNA methylation. Comprehensive data integration revealed selective chromatin accessibility at enhancers but not at promoters close to state-determining genes. Notably, pathological reactivation of the vasculature during tumor progression required the reestablishment of angiogenic enhancer regions to hijack developmental transcriptional programs. Enhancer reestablishment was associated with the selective expression of chromatin-modifying enzymes and the preservation of DNA hypomethylation and chromatin accessibility at former angiogenic enhancers. The data establish an enhancer-driven model of the endothelial transcriptome during angiogenic to quiescent endothelial state transition, yielding deep mechanistic insight into the dynamic epigenetic landscape governing endothelial cell function and plasticity.