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

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    Author
    Anderson, DJ; Kaplan, DI; Bell, KM; Koutsis, K; Haynes, JM; Mills, RJ; Phelan, DG; Qian, EL; Leitoguinho, AR; Arasaratnam, D; ...
    Date
    2018-04-10
    Source Title
    Nature Communications
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Cheung, Michael; Porrello, Enzo; Curl, Claire; Oshlack, Alicia; Petrou, Steven; Elliott, David; Kaplan, David; Delbridge, Leanne; Elefanty, Andrew; Stanley, Edouard
    Affiliation
    Florey Department of Neuroscience and Mental Health
    Paediatrics (RCH)
    Physiology
    School of Physics
    Metadata
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    Document Type
    Journal Article
    Citations
    Anderson, D. J., Kaplan, D. I., Bell, K. M., Koutsis, K., Haynes, J. M., Mills, R. J., Phelan, D. G., Qian, E. L., Leitoguinho, A. R., Arasaratnam, D., Labonne, T., Ng, E. S., Davis, R. P., Casini, S., Passier, R., Hudson, J. E., Porrello, E. R., Costa, M. W., Rafii, A. ,... Elliott, D. A. (2018). NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network. NATURE COMMUNICATIONS, 9 (1), https://doi.org/10.1038/s41467-018-03714-x.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/254807
    DOI
    10.1038/s41467-018-03714-x
    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.

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    • Paediatrics (RCH) - Research Publications [2391]
    • Florey Department of Neuroscience and Mental Health - Research Publications [1300]
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