Epigenetic regulation of "differentiation timing" of cardiovascular cells

细胞分化的速度受到严格控制，对正常发育和干细胞分化至关重要。然而，调控分化速度的潜在机制是完全未知的。在这里，我们展示了决定小鼠胚胎干细胞分化速度的分子机制。蛋白激酶A(PKA)的激活加快了分化速度，导致中胚层和其他生殖层细胞提前2倍出现，与ESC分化后多能标志的提前消失相互关联。在Oct3/4和Nanog基因启动子中，PKA激活增加了H3K9甲基转移酶G9a的蛋白表达，以及早期的H3K9二甲基化和DNA甲基化。G9a的缺失完全消除了PKA诱导的分化加速和表观遗传修饰。此外，G9a基因敲除小鼠在胚胎第7天表现出Oct3/4和Nanog的表达延长。5、发展滞后。

Velocity of cell differentiation is strictly controlled and is crucial for normal development and stem cell differentiation. However, underlying mechanisms regulating differentiation velocity are fully unknown. Here we show a molecular mechanism determining differentiation velocity from mouse embryonic stem cells(ESCs). Activation of protein kinase A(PKA) accelerates differentiation velocity to induce approximately 2-times earlier appearance of mesoderm and other germ layer cells, reciprocally correlated with the earlier disappearance of pluripotent markers after ESC differentiation. PKA activation increased protein expression of G9a, a H3K9 methyltransferase, along with earlier H3K9 dimethylation and DNA methylation in Oct3/4 and Nanog gene promoters. Deletion of G9a completely abolished PKA-elicited acceleration of differentiation and epigenetic modification. Furthermore, G9a knockout mice showed prolonged expressions of Oct3/4 and Nanog at embryonic day-7. 5 and delayed development.