ॐ↑ HACS ↑ ॐ
|文章標題：
Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells.
|核心內容：
多能性喪失是一個漸進的事件，其啟動因素在很大程度上是未知的。在這裡，我們報導了在分化的最初幾個小時內誘導的最早的代謝變化。高解析度核磁共振鑑定了44種代謝物，並在早期分化過程中發生了明顯的代謝轉變。代謝和轉錄分析表明，多能細胞通過糖酵解產生乙醯輔酶A，並在分化過程中迅速喪失這一功能。重要的是，糖酵解的調節阻止了人類和小鼠胚胎幹細胞中組蛋白的去乙醯化和分化。乙酸乙酯是乙醯輔酶A的前體，它以劑量依賴的方式延遲分化並阻斷組蛋白的早期脫乙醯化。乙醯輔酶A上遊的抑制劑誘導多能細胞分化，下遊的抑制劑延遲分化。我們的結果顯示，在分化的最初幾個小時，代謝開關導致組蛋白乙醯化和多能性狀態的喪失。我們的數據強調了代謝在多能性中的重要作用，並提示控制組蛋白乙醯化的糖酵解開關可以使幹細胞從多能性中釋放出來。Loss of pluripotency is a gradual event whose initiating factors are largely unknown. Here we report the earliest metabolic changes induced during the first hours of differentiation. High-resolution NMR identified 44 metabolites and a distinct metabolic transition occurring during early differentiation. Metabolic and transcriptional analyses showed that pluripotent cells produced acetyl-CoA through glycolysis and rapidly lost this function during differentiation. Importantly, modulation of glycolysis blocked histone deacetylation and differentiation in human and mouse embryonic stem cells. Acetate, a precursor of acetyl-CoA, delayed differentiation and blocked early histone deacetylation in a dose-dependent manner. Inhibitors upstream of acetyl-CoA caused differentiation of pluripotent cells, while those downstream delayed differentiation. Our results show a metabolic switch causing a loss of histone acetylation and pluripotent state during the first hours of differentiation. Our data highlight the important role metabolism plays in pluripotency and suggest that a glycolytic switch controlling histone acetylation can release stem cells from pluripotency.
參考文獻：10.1016/j.cmet.2015.02.002
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