Self-renewing embryonic stem cells (ESCs) respond to environmental cues by exiting pluripotency or entering a quiescent state. The molecular basis underlying this fate choice remains unclear. Here, we show that histone acetyltransferase MOF plays a critical role in this process through directly activating fatty acid oxidation (FAO) in the ground-state ESCs. We further show that the ground-state ESCs particularly rely on elevated FAO for oxidative phosphorylation (OXPHOS) and energy production. Mof deletion or FAO inhibition induces bona fide quiescent ground-state ESCs with an intact core pluripotency network and transcriptome signatures akin to the diapaused epiblasts in vivo. Mechanistically, MOF/FAO inhibition acts through reducing mitochondrial respiration (i.e., OXPHOS), which in turn triggers reversible pluripotent quiescence specifically in the ground-state ESCs. The inhibition of FAO/OXPHOS also induces quiescence in naive human ESCs. Our study suggests a general function of the MOF/FAO/OXPHOS axis in regulating cell fate determination in stem cells.

自我更新胚胎干细胞 (ESC) 通过退出多能性或进入静止状态来响应环境线索。这种命运选择的分子基础仍不清楚。在这里，我们表明组蛋白乙酰转移酶 MOF 通过直接激活基态 ESC 中的脂肪酸氧化 (FAO) 在这一过程中发挥关键作用。我们进一步表明，基态 ESCs 特别依赖于升高的 FAO 进行氧化磷酸化 (OXPHOS) 和能量生产。Mof缺失或FAO抑制诱导真正的静止基态ESC具有完整的核心多能网络和类似于体内滞育外胚层的转录组特征. 从机制上讲，MOF/FAO 抑制通过减少线粒体呼吸（即 OXPHOS）起作用，这反过来又在基态 ESC 中触发可逆的多能静息。对FAO/OXPHOS 的抑制也会在幼稚的人类胚胎干细胞中诱导静止。我们的研究表明 MOF/FAO/OXPHOS 轴在调节干细胞中细胞命运决定方面的一般功能。