6月14日，Cell Stem Cell雜志報道了干細(xì)胞分化時機調(diào)控機制的最新進展,。細(xì)胞分化的時機受到嚴(yán)格的調(diào)控,。這對正常的發(fā)育和干細(xì)胞分化至關(guān)重要。然而,，這種調(diào)控的機理完全不清楚,。
本研究揭示了決定小鼠胚胎干細(xì)胞（ESC）分化時機的分子機制。蛋白激酶A（PKA）的激活調(diào)節(jié)分化時機,，加速中胚層及其他胚層細(xì)胞的出現(xiàn),。這與ESC分化后多能性標(biāo)志物的早期消失是相互關(guān)聯(lián)的。
PKA活化增加了G9a,一種H3K9甲基轉(zhuǎn)移酶,，的表達,。伴隨的是H3K9的雙甲基化和Oct3/4和Nanog基因啟動子位點DNA的甲基化。敲除G9a將完全抑制PKA引發(fā)的分化進程和表觀遺傳修飾,。而且,，G9a敲除小鼠在胚胎期7.5天呈現(xiàn)延長的Oct3/4和Nanog基因表達,，以及發(fā)育延遲。
總之,，本研究證實,，調(diào)節(jié)多系譜分化時機的分子機器是通過聯(lián)系信號通路和表觀遺傳修飾運作的。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
PMC:
PMID:
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.
