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Atrial septal defects (ASDs) are a common human congenital heart disease (CHD) that can be induced by genetic abnormalities. Our previous studies have demonstrated a genetic interaction between  Tbx5  and  Osr1  in the second heart field (SHF) for atrial septation. We hypothesized that  Osr1  and  Tbx5  share a common signaling networking and downstream targets for atrial septation. To identify this molecular networks, we acquired the RNA-Seq transcriptome data from the posterior SHF of  wild-type ,  Tbx5 +/   − ,  Osr1 +/−  ,  Osr1 −/−   and  Tbx5 +/− /Osr1 +/−   mutant embryos. Gene set analysis was used to identify the Kyoto Encyclopedia of Genes and Genomes pathways that were affected by the doses of  Tbx5  and  Osr1 . A gene network module involving  Tbx5  and  Osr1  was identified using a non-parametric distance metric, distance correlation. A subset of 10 core genes and gene–gene interactions in the network module were validated by gene expression alterations in posterior second heart field (pSHF) of  Tbx5  and  Osr1  transgenic mouse embryos, a time-course gene expression change during P19CL6 cell differentiation.  Pcsk6  was one of the network module genes that were linked to Tbx5. We validated the direct regulation of  Tbx5  on  Pcsk6  using immunohistochemical staining of pSHF, ChIP-quantitative polymerase chain reaction and luciferase reporter assay. Importantly, we identified  Pcsk6  as a novel gene associated with ASD via a human genotyping study of an ASD family. In summary, our study implicated a gene network involving  Tbx5 ,  Osr1  and  Pcsk6  interaction in SHF for atrial septation, providing a molecular framework for understanding the role of Tbx5 in CHD ontogeny.

Gene network and familial analyses uncover a gene network involving Tbx5/Osr1/Pcsk6 interaction in the second heart field for atrial septation