title: Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency.
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.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA; Program in Developmental and Stem Cell Biology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Christina V
authors.initials: CV
authors.lastname: Theodoris
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
authors.forename: Molong
authors.initials: M
authors.lastname: Li
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: White
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: He
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Pollard
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA; Program in Developmental and Stem Cell Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA; Program in Developmental and Stem Cell Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: dsrivastava@gladstone.ucsf.edu.
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
mesh_terms: D042783:Endothelial Cells / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D053263:Gene Regulatory Networks; D057895:Haploinsufficiency; D042421:Histone Code; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D008297:Male; D010012:Osteogenesis; D010375:Pedigree; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D013314:Stress, Mechanical; D014158:Transcription, Genetic
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1