Department of Pediatrics, David Geffen School of Medicine, University of California, 10833 Le Conte Ave, MDCC-B2-375, Los Angeles, CA, 90095, USA.
Neonatal/Congenital Heart Laboratory, Cardiovascular Research Laboratory, University of California, Los Angeles, CA, USA.
J Mol Med (Berl). 2019 Dec;97(12):1711-1722. doi: 10.1007/s00109-019-01857-y. Epub 2019 Dec 13.
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.
先天性心脏病（CHD）的表型谱是由遗传和环境因素共同贡献的。它们的相互作用是非常异质的，但可能在共同的途径上运作，例如在 CHD 背景下出生后心脏发育中的缺氧信号转导。法洛四联症（TOF）是最常见的发绀（缺氧）CHD。然而，缺氧环境如何在出生后导致 TOF 发病机制尚不清楚。我们对发绀和非发绀 TOF 的右心室流出道（RVOT）标本进行了全基因组转录组分析。共表达网络分析确定了与 TOF 心脏临床诊断和低氧血症状态特别相关的基因模块。特别是，肌细胞增殖的缺氧依赖性诱导与 E2F1 介导的细胞周期调节和 WNT11-RB1 轴的抑制有关。在发绀性 TOF 患者中，还抑制了富含上皮间质转化（EMT）、纤维化和肌节的基因。重要的是，缺氧调节模块的转录因子分析表明 CREB1 是缺氧/WNT11-RB1 电路的潜在调节因子。该研究提供了与 TOF 表型相关的转录组编程的高分辨率图谱，并揭示了发绀性 TOF 中的缺氧诱导调节回路。缺氧诱导的心肌细胞增殖涉及 WNT11-RB1 轴上游 CREB1 活性的负调节。
遗传和环境因素共同导致先天性心脏病（CHD）。出生后缺氧如何导致法洛四联症（TOF）发病机制尚不清楚。基于系统生物学的分析揭示了 CHD 中的独特分子特征。发现与发绀性 TOF 特别相关的基因表达模块。揭示了出生后 TOF 发病机制中缺氧诱导的关键调节回路。
