Department of Pathology, University of Washington, Seattle, 98109, USA.
Cell. 2012 Sep 28;151(1):221-32. doi: 10.1016/j.cell.2012.08.027. Epub 2012 Sep 11.
Directed differentiation of human embryonic stem cells (ESCs) into cardiovascular cells provides a model for studying molecular mechanisms of human cardiovascular development. Although it is known that chromatin modification patterns in ESCs differ markedly from those in lineage-committed progenitors and differentiated cells, the temporal dynamics of chromatin alterations during differentiation along a defined lineage have not been studied. We show that differentiation of human ESCs into cardiovascular cells is accompanied by programmed temporal alterations in chromatin structure that distinguish key regulators of cardiovascular development from other genes. We used this temporal chromatin signature to identify regulators of cardiac development, including the homeobox gene MEIS2. Using the zebrafish model, we demonstrate that MEIS2 is critical for proper heart tube formation and subsequent cardiac looping. Temporal chromatin signatures should be broadly applicable to other models of stem cell differentiation to identify regulators and provide key insights into major developmental decisions.
人胚胎干细胞（ESC）的定向分化为心血管细胞提供了研究人类心血管发育分子机制的模型。尽管已知 ESC 中的染色质修饰模式与谱系定向祖细胞和分化细胞中的明显不同，但沿着特定谱系分化过程中染色质改变的时间动态尚未被研究。我们表明，人 ESC 向心血管细胞的分化伴随着染色质结构的程序性时间改变，这些改变将心血管发育的关键调节剂与其他基因区分开来。我们使用这种时间染色质特征来鉴定心脏发育的调节剂，包括同源盒基因 MEIS2。使用斑马鱼模型，我们证明 MEIS2 对于心脏管形成和随后的心脏环化是至关重要的。时间染色质特征应该广泛适用于其他干细胞分化模型，以鉴定调节剂并为主要发育决策提供关键见解。
