NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network.
NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network.
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DOI：
10.1038/s41467-018-03714-x
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发表时间：
2018-04-10
影响因子：
16.6
通讯作者：
Elliott DA
中科院分区：
文献类型：
--
作者：
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
先天性心脏缺陷可由指导心脏谱系形成的基因突变引起。在这里，我们发现在人胚胎干细胞（hESCs）中缺失NKX2-5（心脏基因调控网络的一个关键组成部分）会导致心肌发生受损，无法激活VCAM1并下调祖细胞标志物PDGFRα。此外，NKX2-5缺失的心肌细胞有异常的生理，具有异步收缩和改变的动作电位。分子分析和遗传拯救实验表明bHLH蛋白HEY2是NKX2-5功能在人类心肌形成过程中的关键介质。这些发现确定了HEY2是NKX2-5心脏转录网络的一个新组成部分，为hESC模型可以破译调节早期人类心脏发育的复杂途径提供了切实的证据。这些数据为评估先天性心脏病致病性突变提供了人类背景。包括转录因子Nkx2-5在内的基因调控网络调节心脏发育。在这里，作者表明，在人类胚胎干细胞中缺失NKX2-5后，心肌发生受损，动作电位改变，这是通过HEY2调节的。
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. A gene regulatory network, including the transcription factor Nkx2-5, regulates cardiac development. Here, the authors show that on deletion of NKX2-5 from human embryonic stem cells, there is impaired cardiomyogenesis and changes in action potentials, and that this is regulated via HEY2.
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影响因子：
20.1
作者：
Kathiriya IS;Nora EP;Bruneau BG
通讯作者：
Bruneau BG
影响因子：
2.7
作者：
Clark, Christopher D.;Zhang, Boding;Lee, Benjamin;Evans, Samuel I.;Lassar, Andrew B.;Lee, Kyu-Ho
通讯作者：
Lee, Kyu-Ho
影响因子：
11.8
作者：
DeLaughter, Daniel M.;Bick, Alexander G.;Wakimoto, Hiroko;McKean, David;Gorham, Joshua M.;Kathiriya, Irian S.;Hinson, John T.;Homsy, Jason;Gray, Jesse;Pu, William;Bruneau, Benoit G.;Seidman, J. G.;Seidman, Christine E.
通讯作者：
Seidman, Christine E.
影响因子：
14.8
作者：
Davis, Richard P.;Costa, Magdaline;Stanley, Edouard G.
通讯作者：
Stanley, Edouard G.
影响因子：
2.7
作者：
Bruneau, BG;Bao, ZZ;Seidman, CE
通讯作者：
Seidman, CE