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

David J. Anderson, David I. Kaplan, Katrina M. Bell, Katerina Koutsis, John M. Haynes, Richard J. Mills, Dean G. Phelan, Elizabeth L. Qian, Ana Rita Leitoguinho, Deevina Arasaratnam, Tanya Labonne, Elizabeth S. Ng, Richard P. Davis, Simona Casini, Robert Passier, James E. Hudson, Enzo R. Porrello, Mauro W. Costa, Arash Rafii, Clare L. CurlLea M. Delbridge, Richard P. Harvey, Alicia Oshlack, Michael M. Cheung, Christine L. Mummery, Stephen Petrou, Andrew G. Elefanty, Edouard G. Stanley, David A. Elliott*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

21 Citations (Scopus)
6 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article number1373
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - 10 Apr 2018
Externally publishedYes

Fingerprint Dive into the research topics of 'NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network'. Together they form a unique fingerprint.

  • Cite this

    Anderson, D. J., Kaplan, D. I., Bell, K. M., Koutsis, K., Haynes, J. M., Mills, R. J., ... Elliott, D. A. (2018). NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network. Nature communications, 9(1), [1373]. https://doi.org/10.1038/s41467-018-03714-x