NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network

• Published in: Nature communications Vol. 9; no. 1; pp. 1373 - 13
• Main Authors: Anderson, David J., Kaplan, David I., Bell, Katrina M., Koutsis, Katerina, Haynes, John M., Mills, Richard J., Phelan, Dean G., Qian, Elizabeth L., Leitoguinho, Ana Rita, Arasaratnam, Deevina, Labonne, Tanya, Ng, Elizabeth S., Davis, Richard P., Casini, Simona, Passier, Robert, Hudson, James E., Porrello, Enzo R., Costa, Mauro W., Rafii, Arash, Curl, Clare L., Delbridge, Lea M., Harvey, Richard P., Oshlack, Alicia, Cheung, Michael M., Mummery, Christine L., Petrou, Stephen, Elefanty, Andrew G., Stanley, Edouard G., Elliott, David A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.04.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/106; 13/107; 14/35; 38/39; 45/15; 631/136/142; 631/208/135; 631/443/592/75/1539; 9/30; 9/74; 96/31; Action Potentials - physiology; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cardiomyocytes; Cell Differentiation; Cell Line; Clonal deletion; Coronary artery disease; Critical components; Developmental stages; Embryo cells; Gene Deletion; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Heart; Heart diseases; Homeobox Protein Nkx-2.5 - deficiency; Homeobox Protein Nkx-2.5 - genetics; Human Embryonic Stem Cells - cytology; Human Embryonic Stem Cells - metabolism; Humanities and Social Sciences; Humans; multidisciplinary; Mutation; Myocardium - cytology; Myocardium - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Nkx2.5 protein; Organogenesis - genetics; Patch-Clamp Techniques; Receptor, Platelet-Derived Growth Factor alpha - genetics; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Science; Science (multidisciplinary); Stem cells; Transcription; Transcription, Genetic; Vascular Cell Adhesion Molecule-1 - genetics; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03714-x

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 HEY2 is a key mediator of NKX2-5 function during human cardiomyogenesis. These findings identify HEY2 as a novel component of the NKX2-5 cardiac transcriptional network, providing tangible evidence that hESC models can decipher the 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. A gene regulatory network, including the transcription factor Nkx2-5 , regulates cardiac development. Here, the authors show that on deletion of NKX2-5 from human embryonic stem cells, there is impaired cardiomyogenesis and changes in action potentials, and that this is regulated via HEY2 .