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gene-environment regulatory circuits of right ventricular pathology in tetralogy of fallot
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نویسنده
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zhao yan ,kang xuedong ,gao fuying ,guzman alejandra ,lau ryan p. ,biniwale reshma ,wadehra madhuri ,reemtsen brian ,garg meena ,halnon nancy ,quintero-rivera fabiola ,arsdell glen van ,coppola giovanni ,nelson stanley f. ,touma marlin ,faculty the ucla congenital heart defects biocore
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منبع
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journal of molecular medicine - 2019 - دوره : 97 - شماره : 12 - صفحه:1711 -1722
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چکیده
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The phenotypic spectrum of congenital heart defects (chds) is contributed by both genetic and environmental factors. their interactions are profoundly heterogeneous but 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.
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کلیدواژه
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congenital heart defects ,genome ,transcriptome ,tetralogy of fallot ,hypoxia
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آدرس
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university of california, david geffen school of medicine, department of pediatrics, neonatal/congenital heart laboratory, cardiovascular research laboratory, usa, university of california, david geffen school of medicine, department of pediatrics, neonatal/congenital heart laboratory, cardiovascular research laboratory, usa, university of california, david geffen school of medicine, department of neurology, usa, university of california, david geffen school of medicine, department of pediatrics, usa, university of california, clinical genomics center, david geffen school of medicine, department of pathology and laboratory medicine, usa, university of california, david geffen school of medicine, department of cardiothoracic surgery, usa, university of california, clinical genomics center, david geffen school of medicine, department of pathology and laboratory medicine, usa, university of california, david geffen school of medicine, department of cardiothoracic surgery, usa, university of california, david geffen school of medicine, department of pediatrics, usa, university of california, david geffen school of medicine, department of pediatrics, usa, university of california, clinical genomics center, david geffen school of medicine, department of pathology and laboratory medicine, usa, university of california, david geffen school of medicine, department of cardiothoracic surgery, usa, university of california, david geffen school of medicine, department of neurology, usa, university of california, david geffen school of medicine, institute of precision health, david geffen school of medicine, institute of precision health, david geffen school of medicine, department of pediatrics, department of neurology, department of human genetics, usa
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Authors
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