6月14日，Cell Stem Cell杂志报道了干细胞分化时机调控机制的最新进展。细胞分化的时机受到严格的调控。这对正常的发育和干细胞分化至关重要。然而，这种调控的机理完全不清楚。
本研究揭示了决定小鼠胚胎干细胞（ESC）分化时机的分子机制。蛋白激酶A（PKA）的激活调节分化时机，加速中胚层及其他胚层细胞的出现。这与ESC分化后多能性标志物的早期消失是相互关联的。
PKA活化增加了G9a,一种H3K9甲基转移酶，的表达。伴随的是H3K9的双甲基化和Oct3/4和Nanog基因启动子位点DNA的甲基化。敲除G9a将完全抑制PKA引发的分化进程和表观遗传修饰。而且，G9a敲除小鼠在胚胎期7.5天呈现延长的Oct3/4和Nanog基因表达，以及发育延迟。
总之，本研究证实，调节多系谱分化时机的分子机器是通过联系信号通路和表观遗传修饰运作的。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
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Protein Kinase A Determines Timing of Early Differentiation through Epigenetic Regulation with G9a
Kohei Yamamizu, Mayako Fujihara, Makoto Tachibana, Shiori Katayama, Akiko Takahashi, Eiji Hara, Hiroshi Imai, et al.
Timing of cell differentiation is strictly controlled and is crucial for normal development and stem cell differentiation. However, underlying mechanisms regulating differentiation timing are fully unknown. Here, we show a molecular mechanism determining differentiation timing from mouse embryonic stem cells (ESCs). Activation of protein kinase A (PKA) modulates differentiation timing to accelerate the appearance of mesoderm and other germ layer cells, reciprocally correlated with the earlier disappearance of pluripotent markers after ESC differentiation. PKA activation increases protein expression of G9a, an H3K9 methyltransferase, along with earlier H3K9 dimethylation and DNA methylation in Oct3/4 and Nanog gene promoters. Deletion of G9a completely abolishes PKA-elicited acceleration of differentiation and epigenetic modification. Furthermore, G9a knockout mice show prolonged expressions of Oct3/4 and Nanog at embryonic day 7.5 and delayed development. In this study, we demonstrate molecular machinery that regulates timing of multilineage differentiation by linking signaling with epigenetics.
