Heterozygous nonsense mutations in NOTCH1 cause bicuspid aortic valve and aortic valve calcification. Now, Deepak Srivastava and colleagues report the use of human induced pluripotent stem cell (iPSC) models to investigate how NOTCH1 haploinsufficiency causes aortic valve calcification (Cell 160, 1072–1086, 2015). The authors derived human endothelial cells in vitro and characterized them using RNA sequencing and ChIP-seq for H3K4me3, H3K27ac, H3K4me1 and H3K27me3 histone modifications. They also generated iPSC-derived endothelial cells from three individuals with heterozygous nonsense mutations in NOTCH1 and created isogenic control lines by correcting the mutations using TALENs. They found that exposure to shear stress, which is known to protect against aortic valve calcification in vivo, alters the epigenetic state and suppresses the expression of components of osteogenic and inflammatory pathways when applied in vitro to normal human endothelial cells. In contrast, exposure to shear stress dysregulated the epigenetic state and caused aberrant upregulation of components of osteogenic and inflammatory signaling pathways in NOTCH1-mutated cells. Finally, the authors used network modeling to identify three putative regulatory node genes aberrantly upregulated by NOTCH1 heterozygosity and showed that siRNA-mediated downregulation of these targets restored gene expression in NOTCH1-heterozygous cells toward the normal state.