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 & 9 others Lea M. Delbridge, Richard P. Harvey, Alicia Oshlack, Michael M. Cheung, Christine L. Mummery, Stephen Petrou, Andrew G. Elefanty, Edouard G. Stanley, David A. Elliott

Research output: Contribution to journalArticleResearchpeer-review

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
Number of pages13
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 10 Apr 2018

Keywords

  • congenital heart defects
  • development
  • differentiation

Cite this

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. / NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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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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Anderson, DJ, Kaplan, DI, Bell, KM, Koutsis, K, Haynes, JM, Mills, RJ, Phelan, DG, Qian, EL, Leitoguinho, AR, Arasaratnam, D, Labonne, T, Ng, ES, Davis, RP, Casini, S, Passier, R, Hudson, JE, Porrello, ER, Costa, MW, Rafii, A, Curl, CL, Delbridge, LM, Harvey, RP, Oshlack, A, Cheung, MM, Mummery, CL, Petrou, S, Elefanty, AG, Stanley, EG & Elliott, DA 2018, 'NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network' Nature Communications, vol. 9, no. 1, 1373. https://doi.org/10.1038/s41467-018-03714-x

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

In: Nature Communications, Vol. 9, No. 1, 1373, 10.04.2018.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Anderson, David J.

AU - Kaplan, David I.

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AU - Koutsis, Katerina

AU - Haynes, John M.

AU - Mills, Richard J.

AU - Phelan, Dean G.

AU - Qian, Elizabeth L.

AU - Leitoguinho, Ana Rita

AU - Arasaratnam, Deevina

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AU - Davis, Richard P.

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AU - Passier, Robert

AU - Hudson, James E.

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AU - Costa, Mauro W.

AU - Rafii, Arash

AU - Curl, Clare L.

AU - Delbridge, Lea M.

AU - Harvey, Richard P.

AU - Oshlack, Alicia

AU - Cheung, Michael M.

AU - Mummery, Christine L.

AU - Petrou, Stephen

AU - Elefanty, Andrew G.

AU - Stanley, Edouard G.

AU - Elliott, David A.

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AB - 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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