Gene-Environment Regulatory Circuit of Right Ventricular Pathology in Cyanotic Congenital Heart Defects

Introduction: The phenotypic spectrum of congenital heart defects (CHDs) is contributed by both genetic and environmental factors. Their contributions are profoundly heterogeneous but may operate on common pathways that are not well understood. Elucidating the gene-environment interplays in CHDs pathogenesis is essential to identify chamber specific therapies. Methods: Following the UCLA CHD-BioCore approved protocol, right ventricle outflow tracts (RVOTs) samples were collected from infants with tetralogy of fallot (TOF) or Ventricular Septal Defect (VSD). Total RNA was used for RNA-seq. Systemic hypoxia was induced using hypoxia chamber. Weighted gene network co-expression analysis was performed using R package. Results: Genome-wide transcriptome analysis of RVOT samples from cyanotic and non-cyanotic CHDs uncovers disease-associated differences in gene expression. Co-expression network analysis reveals that individuals with CHDs show diagnosis-specific and environment-specific gene modules. In particular, hypoxia-dependent induction of proliferation and E2F1 dependent cell cycle reprograming are inversely associated with WNT11 signaling in the cyanotic TOF. In addition, epithelial mesenchymal transition (EMT), fibrosis and apoptosis are repressed. Importantly, perinatal hypoxia attenuates the baseline differences between ventricular chambers in neonatal mouse heart. Remarkably, the observed attenuation of ventricular patterning (AVP) genes is more robust in the right ventricle and highly concordant in hypoxemic hearts in mouse and human. Transcriptional dysregulation of the P53 network is a shared hallmark among AVP genes and cyanotic TOF modules. Importantly, P53 network analysis suggests CREB1, a hypoxia sensor, and LEF1, an EMT regulator during cardiogenesis, as potential mediators of hypoxia-Wnt11 circuit. Finally, the data demonstrate that genetic subtypes of TOF may influence hypoxia-induced regulation leading to phenotypic heterogeneity at molecular and cellular levels in cyanotic TOF hearts. Conclusions: Gene-environment interrelations may influence changes in regional gene expression leading to phenotypic heterogeneity at the molecular cellular level in complex cyanotic CHDs.