Journal article
NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network
DJ Anderson, DI Kaplan, KM Bell, K Koutsis, JM Haynes, RJ Mills, DG Phelan, EL Qian, AR Leitoguinho, D Arasaratnam, T Labonne, ES Ng, RP Davis, S Casini, R Passier, JE Hudson, ER Porrello, MW Costa, A Rafii, CL Curl Show all
Nature Communications | Published : 2018
Open access
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 car..
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Awarded by State Government of Victoria
Funding Acknowledgements
Supported by the Victorian Government's Operational Infrastructure Support Program and Australian Government National Health and Medical Research Council (NHMRC) Independent Research Institute Infrastructure Support Scheme (IRIISS). D.J.A. supported by the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement PIOF-GA-2010-276186. R.P.H. supported by grants from the NHMRC (1074386; 573732) and the Australian Research Council Strategic Initiative in Stem Cell Science (SR110001002). R.P.H. held an NHMRC Australia Fellowship (573705). A.G.E. and E.G.S. are Senior Research Fellows of the NHMRC. Qatar National Research Fund (NPRP 09-1087-3-274) supported D.A.E., A.R., E.G.S. Research in the laboratories of D.A.E., A.G.E. and E.G.S. was supported by the NHMRC, the Australian Research Council Strategic Initiative in Stem Cell Science (SR110001002) and the Stafford Fox Medical Research Foundation. The Royal Children's Hospital Foundation and Paceline provided support for D.A.E. and M.M.C.