New aspects of transcriptional control by Tbx5

在心脏发育的早期阶段，遗传程序调节心肌细胞的分化和心管的初始形态发生。然而，一旦心跳开始，心跳和/或血液循环产生的物理力就成为控制心脏发育的几个方面的表观遗传因素。在这个项目中，我们发现MKL2是心脏发生的关键调节因子之一Tbx5的强大辅助激活因子。有趣的是，MKL2以机械刺激依赖的方式在细胞质和细胞核之间穿梭。在斑马鱼心脏中，当心跳停止时，MKL2在细胞质中，而在心跳存在时，MKL2在细胞核中，这表明Tbx5在跳动的心肌细胞中是活跃的。此外，压力超载对小鼠左心室也会导致Tbx5的核穿梭，突出了MKL2作为机械信号的传送器。为了扩大我们对物理力的了解，我们鉴定了几个转录因子，它们在拉伸和剪切应力下穿梭到细胞核中。此外，我们还发现，在心脏发育过程中，一些miRNAs被物理力量诱导(例如，当心跳停止时miR-21的表达被关闭，但却被心跳快速而强烈地诱导)。在这个项目中，我们发现了几个关键的力依赖的心脏发生调控因子，这将为探索对发育和动态平衡至关重要的新的信号转导系统开辟新的途径。

In the early stages of cardiac development, the genetic program regulates differentiation of cardiomyocytes and the initial morphogenesis of heart tube. However, once heartbeat commences, physical forces generated by heartbeat and/or blood circulation become an epigenetic factor that control several aspects of heart development.In this project, we have identified MKL2 as a robust co-activator for Tbx5, one of the key regulators of cardiogenesis. Interestingly, MKL2 shuttles between cytoplasm and nucleus, in a mechanical stimulus-dependent way. In zebrafish heart, MKL2 is in the cytoplasm when heartbeat is arrested, whereas it is in the nucleus in the presence of heartbeat, indicating that Tbx5 is active in the beating cardiomyocyte. In addition, pressure-overload to the left ventricle of mouse hearts also induces nuclear shuttling of Tbx5, highlighting MKL2 as a transducer of mechanical signals.To expand our knowledge on physical forces, we have identified several transcription factors that shuttle into nucleus in response to stretch and shear stresses. In addition, we also found that several miRNAs are induced in developing heart by physical forces (For example, expression of miR-21 is turned off when heartbeat is arrested, yet is rapidly and strongly induced by heartbeat.).In this project, we discovered several key force-dependent regulators of cardiogenesis, which will open a new way to explore a novel signal transduction system that is essential for development and homeostasis.