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Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency.
Theodoris, Christina V; Li, Molong; White, Mark P; Liu, Lei; He, Daniel; Pollard, Katherine S; Bruneau, Benoit G; Srivastava, Deepak.
Afiliação
  • Theodoris CV; 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.
  • Li M; 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.
  • White MP; 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.
  • Liu L; 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.
  • He D; 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.
  • Pollard KS; 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.
  • Bruneau BG; 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; Depart
  • Srivastava D; 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; Depart
Cell ; 160(6): 1072-86, 2015 Mar 12.
Article em En | MEDLINE | ID: mdl-25768904
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Epigênese Genética / Receptor Notch1 / Redes Reguladoras de Genes Tipo de estudo: Prognostic_studies Limite: Female / Humans / Male Idioma: En Revista: Cell Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Epigênese Genética / Receptor Notch1 / Redes Reguladoras de Genes Tipo de estudo: Prognostic_studies Limite: Female / Humans / Male Idioma: En Revista: Cell Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos