Takeuchi Jun K, Bruneau Benoit G
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.
Nature. 2009 Jun 4;459(7247):708-11. doi: 10.1038/nature08039. Epub 2009 Apr 26.
Heart disease is the leading cause of mortality and morbidity in the western world. The heart has little regenerative capacity after damage, leading to much interest in understanding the factors required to produce new cardiac myocytes. Despite a robust understanding of the molecular networks regulating cardiac differentiation, no single transcription factor or combination of factors has been shown to activate the cardiac gene program de novo in mammalian cells or tissues. Here we define the minimal requirements for transdifferentiation of mouse mesoderm to cardiac myocytes. We show that two cardiac transcription factors, Gata4 and Tbx5, and a cardiac-specific subunit of BAF chromatin-remodelling complexes, Baf60c (also called Smarcd3), can direct ectopic differentiation of mouse mesoderm into beating cardiomyocytes, including the normally non-cardiogenic posterior mesoderm and the extraembryonic mesoderm of the amnion. Gata4 with Baf60c initiated ectopic cardiac gene expression. Addition of Tbx5 allowed differentiation into contracting cardiomyocytes and repression of non-cardiac mesodermal genes. Baf60c was essential for the ectopic cardiogenic activity of Gata4 and Tbx5, partly by permitting binding of Gata4 to cardiac genes, indicating a novel instructive role for BAF complexes in tissue-specific regulation. The combined function of these factors establishes a robust mechanism for controlling cellular differentiation, and may allow reprogramming of new cardiomyocytes for regenerative purposes.
在西方世界，心脏病是导致死亡和发病的主要原因。心脏受损后再生能力微弱，这引发了人们对了解生成新心肌细胞所需因素的浓厚兴趣。尽管对调控心脏分化的分子网络已有深入了解，但尚未有单一转录因子或因子组合能在哺乳动物细胞或组织中从头激活心脏基因程序。在此，我们明确了小鼠中胚层向心肌细胞转分化的最低要求。我们发现，两种心脏转录因子Gata4和Tbx5，以及BAF染色质重塑复合物的一个心脏特异性亚基Baf60c（也称为Smarcd3），能够引导小鼠中胚层异位分化为跳动的心肌细胞，包括通常不具有心脏发生能力的后中胚层和羊膜的胚外中胚层。Gata4与Baf60c启动了异位心脏基因表达。添加Tbx5则允许分化为收缩性心肌细胞并抑制非心脏中胚层基因。Baf60c对于Gata4和Tbx5的异位心脏发生活性至关重要，部分原因是它允许Gata4与心脏基因结合，这表明BAF复合物在组织特异性调控中具有新的指导作用。这些因子的联合功能建立了一种强大的控制细胞分化的机制，并且可能允许为了再生目的对新的心肌细胞进行重编程。
