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Gene-environment regulatory circuits of right ventricular pathology in tetralogy of fallot.
Zhao, Yan; Kang, Xuedong; Gao, Fuying; Guzman, Alejandra; Lau, Ryan P; Biniwale, Reshma; Wadehra, Madhuri; Reemtsen, Brian; Garg, Meena; Halnon, Nancy; Quintero-Rivera, Fabiola; Van Arsdell, Glen; Coppola, Giovanni; Nelson, Stanley F; Touma, Marlin.
Afiliação
  • Zhao Y; Department of Pediatrics, David Geffen School of Medicine, University of California, 10833 Le Conte Ave, MDCC-B2-375, Los Angeles, CA, 90095, USA.
  • Kang X; Neonatal/Congenital Heart Laboratory, Cardiovascular Research Laboratory, University of California, Los Angeles, CA, USA.
  • Gao F; Department of Pediatrics, David Geffen School of Medicine, University of California, 10833 Le Conte Ave, MDCC-B2-375, Los Angeles, CA, 90095, USA.
  • Guzman A; Neonatal/Congenital Heart Laboratory, Cardiovascular Research Laboratory, University of California, Los Angeles, CA, USA.
  • Lau RP; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Biniwale R; Department of Pediatrics, David Geffen School of Medicine, University of California, 10833 Le Conte Ave, MDCC-B2-375, Los Angeles, CA, 90095, USA.
  • Wadehra M; Department of Pathology and Laboratory Medicine, Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Reemtsen B; Department of Cardiothoracic Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Garg M; Department of Pathology and Laboratory Medicine, Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Halnon N; Department of Cardiothoracic Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Quintero-Rivera F; Department of Pediatrics, David Geffen School of Medicine, University of California, 10833 Le Conte Ave, MDCC-B2-375, Los Angeles, CA, 90095, USA.
  • Van Arsdell G; Department of Pediatrics, David Geffen School of Medicine, University of California, 10833 Le Conte Ave, MDCC-B2-375, Los Angeles, CA, 90095, USA.
  • Coppola G; Department of Pathology and Laboratory Medicine, Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Nelson SF; Department of Cardiothoracic Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Touma M; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
J Mol Med (Berl) ; 97(12): 1711-1722, 2019 12.
Article em En | MEDLINE | ID: mdl-31834445
ABSTRACT
The phenotypic spectrum of congenital heart defects (CHDs) is contributed by both genetic and environmental factors. Their interactions are profoundly heterogeneous but may operate on common pathways as in the case of hypoxia signaling during postnatal heart development in the context of CHDs. Tetralogy of Fallot (TOF) is the most common cyanotic (hypoxemic) CHD. However, how the hypoxic environment contributes to TOF pathogenesis after birth is poorly understood. We performed Genome-wide transcriptome analysis on right ventricle outflow tract (RVOT) specimens from cyanotic and noncyanotic TOF. Co-expression network analysis identified gene modules specifically associated with clinical diagnosis and hypoxemia status in the TOF hearts. In particular, hypoxia-dependent induction of myocyte proliferation is associated with E2F1-mediated cell cycle regulation and repression of the WNT11-RB1 axis. Genes enriched in epithelial mesenchymal transition (EMT), fibrosis, and sarcomere were also repressed in cyanotic TOF patients. Importantly, transcription factor analysis of the hypoxia-regulated modules suggested CREB1 as a putative regulator of hypoxia/WNT11-RB1 circuit. The study provides a high-resolution landscape of transcriptome programming associated with TOF phenotypes and unveiled hypoxia-induced regulatory circuit in cyanotic TOF. Hypoxia-induced cardiomyocyte proliferation involves negative modulation of CREB1 activity upstream of the WNT11-RB1 axis. KEY MESSAGES Genetic and environmental factors contribute to congenital heart defects (CHDs). How hypoxia contributes to Tetralogy of Fallot (TOF) pathogenesis after birth is unclear. Systems biology-based analysis revealed distinct molecular signature in CHDs. Gene expression modules specifically associated with cyanotic TOF were uncovered. Key regulatory circuits induced by hypoxia in TOF pathogenesis after birth were unveiled.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tetralogia de Fallot / Transcriptoma / Ventrículos do Coração / Hipóxia Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Child / Child, preschool / Female / Humans / Infant / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tetralogia de Fallot / Transcriptoma / Ventrículos do Coração / Hipóxia Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Child / Child, preschool / Female / Humans / Infant / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article