Human Disease Modeling Reveals Integrated Transcriptional and Epigenetic Mechanisms of NOTCH1 Haploinsufficiency
Open accessAbstract
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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Mapping the gene regulatory networks that drive disease progression enables screening for molecules that correct the network by normalizing core regulatory elements, rather than targeting peripheral downstream effectors that may not be disease modifying.
“Mapping the gene regulatory networks that drive disease progression enables screening for molecules that correct the network by normalizing core regulatory elements, rather than targeting peripheral downstream effectors that may not be disease modifying4,5.”
From Transfer learning enables predictions in network biology (2023) · cites this paper as [4]
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Experimental — accuracy not yet measuredThe authors previously mapped the NOTCH1-dependent gene network governing cardiac valve disease and identified central regulatory nodes whose correction had broad restorative impact on the network at large.
“We previously mapped the NOTCH1 (N1)-dependent gene network governing cardiac valve disease and identified central regulatory nodes whose correction had broad restorative impact on the network at large4,5.”
From Transfer learning enables predictions in network biology (2023) · cites this paper as [4]
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- Authors
- Theodoris, C. V., Li, M., White, M. P., Liu, L., He, D., Pollard, K. S., Bruneau, B. G., & Srivastava, D.
- Affiliations
- Gladstone Institutes (US)
- Corresponding author
- Srivastava, Deepak
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 160
- Issue
- 6
- Pages
- 1072-1086
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4359747
- OpenAlex
- W1965115186
- Cited by
- 210
- References
- 68
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 11 · 2023: 9 · 2022: 17 · 2021: 24 · 2020: 24 · 2019: 22 · 2018: 19 · 2017: 25 · 2016: 21 · 2015: 15
- FWCI
- 11.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- University of California, San Francisco
- National Heart, Lung, and Blood Institute (U01HL100406, P01HL089707, HL089707, U01HL098179)
- National Institute of General Medical Sciences (T32GM007618)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007470)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Notch1, haploinsufficiency, aortic valve calcification, iPSC-derived endothelial cells, hemodynamic shear stress, H3K27ac, enhancer regulation, transcription factor dosage, gene regulatory networks, therapeutic target
- MeSH terms
- Female, Humans, Inflammation, Male, Osteogenesis, Pedigree, Stress, Mechanical, Transcription, Genetic, Histone Code, Endothelial Cells, Epigenesis, Genetic, Receptor, Notch1, Gene Regulatory Networks, Induced Pluripotent Stem Cells, Haploinsufficiency
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