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. Curl, Lea M. Delbridge, Richard P. Harvey, Alicia Oshlack, Michael M. Cheung, Christine L. Mummery, Stephen Petrou, Andrew G. Elefanty, Edouard G. Stanley and David A. Elliott ()
Additional contact information
David J. Anderson: Royal Children’s Hospital
David I. Kaplan: University of Melbourne
Katrina M. Bell: Royal Children’s Hospital
Katerina Koutsis: Royal Children’s Hospital
John M. Haynes: Monash University
Richard J. Mills: University of Queensland
Dean G. Phelan: Royal Children’s Hospital
Elizabeth L. Qian: Royal Children’s Hospital
Ana Rita Leitoguinho: Royal Children’s Hospital
Deevina Arasaratnam: Royal Children’s Hospital
Tanya Labonne: Royal Children’s Hospital
Elizabeth S. Ng: Royal Children’s Hospital
Richard P. Davis: Leiden University Medical Center
Simona Casini: Leiden University Medical Center
Robert Passier: Leiden University Medical Center
James E. Hudson: University of Queensland
Enzo R. Porrello: University of Queensland
Mauro W. Costa: The Jackson Laboratory
Arash Rafii: Weill Cornell Medical College in Qatar Qatar Foundation
Clare L. Curl: University of Melbourne
Lea M. Delbridge: University of Melbourne
Richard P. Harvey: Victor Chang Cardiac Research Institute
Alicia Oshlack: Royal Children’s Hospital
Michael M. Cheung: Royal Children’s Hospital
Christine L. Mummery: Leiden University Medical Center
Stephen Petrou: University of Melbourne
Andrew G. Elefanty: Royal Children’s Hospital
Edouard G. Stanley: Royal Children’s Hospital
David A. Elliott: Royal Children’s Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03714-x

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