ArticleCell2015
Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency.
Article in Cell, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 128 papers.
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Who cites it
128 citing papers in PubMed, 209 citations in OpenAlex.
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- Temporal AI model predicts drivers of cell state trajectories across human aging.bioRxiv : the preprint server for biology · 2026Article
- Enhancer Dynamics for Gene Regulation in the Cardiovascular System.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Pathophysiology of androgen-associated endothelial cell dysfunction in phenotype A polycystic ovarian syndrome revealed by iPSCs modeling.Frontiers in endocrinology · 2026Article
- In Vivo Models of Cardiovascular Disease:Biomedicines · 2025Review
- A novel NOTCH1 nonsense variant in a bicuspid aortic valve family with intrafamilial clinical heterogeneity.BMC cardiovascular disorders · 2025Article
- Prenatal nicotine exposure induces epigenetic alterations in the Notch signaling genes in the proximal colon in rats.BMC genomics · 2025Article
- Reversion of aortic valve cells calcification by activation of Notch signalling via histone acetylation induction.Signal transduction and targeted therapy · 2025Article
- Uncovering Developmental Origins of Aortic Valve Disease: A Clinically Relevant Genetic Model of Aortic Stenosis.JACC. Basic to translational science · 2025Article
- Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme inhibitor MLN4924.Scientific reports · 2025Article
- Improved epigenetic age prediction models by combining sex chromosome and autosomal markers.Epigenetics & chromatin · 2025Article
- Transformative Potential of Induced Pluripotent Stem Cells in Congenital Heart Disease Research and Treatment.Children (Basel, Switzerland) · 2025Review
- Cardiac Tissue Engineering for Translational Cardiology: From In Vitro Models to Regenerative Therapies.Bioengineering (Basel, Switzerland) · 2025Review
- Navigating the Landscape of Translational Medicine of Calcific Aortic Valve Disease: Bridging Bench to Bedside.JACC. Asia · 2025Review
- Regulation of histone H3K27 methylation in inflammation and cancer.Molecular biomedicine · 2025Review
- Next-Gen Therapeutics: Pioneering Drug Discovery with iPSCs, Genomics, AI, and Clinical Trials in a Dish.Annual review of pharmacology and toxicology · 2025Review
- GeneCompass: deciphering universal gene regulatory mechanisms with a knowledge-informed cross-species foundation model.Cell research · 2024Article
- Control of spatio-temporal patterning via cell growth in a multicellular synthetic gene circuit.Nature communications · 2024Article
68 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.