Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency

Cell. 2015 Mar 12;160(6):1072-86. doi: 10.1016/j.cell.2015.02.035.


The mechanisms by which transcription factor haploinsufficiency alters the epigenetic and transcriptional landscape in human cells to cause disease are unknown. Here, we utilized human induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) to show that heterozygous nonsense mutations in NOTCH1 that cause aortic valve calcification disrupt the epigenetic architecture, resulting in derepression of latent pro-osteogenic and -inflammatory gene networks. Hemodynamic shear stress, which protects valves from calcification in vivo, activated anti-osteogenic and anti-inflammatory networks in NOTCH1(+/+), but not NOTCH1(+/-), iPSC-derived ECs. NOTCH1 haploinsufficiency altered H3K27ac at NOTCH1-bound enhancers, dysregulating downstream transcription of more than 1,000 genes involved in osteogenesis, inflammation, and oxidative stress. Computational predictions of the disrupted NOTCH1-dependent gene network revealed regulatory nodes that, when modulated, restored the network toward the NOTCH1(+/+) state. Our results highlight how alterations in transcription factor dosage affect gene networks leading to human disease and reveal nodes for potential therapeutic intervention.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Endothelial Cells / metabolism
  • Epigenesis, Genetic*
  • Female
  • Gene Regulatory Networks*
  • Haploinsufficiency
  • Histone Code
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Inflammation / metabolism
  • Male
  • Osteogenesis
  • Pedigree
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism
  • Stress, Mechanical
  • Transcription, Genetic


  • NOTCH1 protein, human
  • Receptor, Notch1