Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Cell Stem Cell. 2020 Sep 3;27(3):441-458.e10. doi: 10.1016/j.stem.2020.06.005. Epub 2020 Jun 30.
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.
自我更新的胚胎干细胞 (ESC) 通过退出多能性或进入静止状态来响应环境信号。这种命运选择的分子基础尚不清楚。在这里，我们表明组蛋白乙酰转移酶 MOF 通过直接激活基础态 ESC 中的脂肪酸氧化 (FAO) 在这个过程中发挥关键作用。我们进一步表明，基础态 ESC 特别依赖于升高的 FAO 进行氧化磷酸化 (OXPHOS) 和能量产生。Mof 缺失或 FAO 抑制诱导真正的静止基础态 ESC，其核心多能性网络和转录组特征类似于体内休眠的上胚层。在机制上，MOF/FAO 抑制通过降低线粒体呼吸（即 OXPHOS）起作用，这反过来又特异性地触发基础态 ESC 中可逆的多能性静止。FAO/OXPHOS 的抑制也会诱导原始人 ESC 静止。我们的研究表明 MOF/FAO/OXPHOS 轴在调节干细胞中的细胞命运决定方面具有普遍功能。
