NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network
2018
Congenital heart defects can be caused by mutations in genes that guide cardiac lineage formation. Here, we show deletion of NKX2-5, a critical component of the cardiac
gene regulatory network, in human
embryonic stem cells(hESCs), results in impaired cardiomyogenesis, failure to activate VCAM1 and to downregulate the progenitor marker PDGFRα. Furthermore, NKX2-5 null cardiomyocytes have abnormal physiology, with asynchronous contractions and altered action potentials. Molecular profiling and genetic rescue experiments demonstrate that the bHLH protein
HEY2is a key mediator of NKX2-5 function during human cardiomyogenesis. These findings identify
HEY2as a novel component of the NKX2-5 cardiac transcriptional network, providing tangible evidence that hESC models can
decipherthe complex pathways that regulate early stage human
heart development. These data provide a human context for the evaluation of pathogenic mutations in congenital heart disease.
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