Histone Acetyltransferase MOF Blocks Acquisition of Quiescence in Ground-State ESCs through Activating Fatty Acid Oxidation


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. Copyright © 2020 Elsevier Inc. All rights reserved.

Authors Khoa LTP, Tsan YC, Mao F, Kremer DM, Sajjakulnukit P, Zhang L, Zhou B, Tong X, Bhanu NV, Choudhary C, Garcia BA, Yin L, Smith GD, Saunders TL, Bielas SL, Lyssiotis CA, Dou Y
Journal Cell stem cell
Publication Date 2020 Sep 3;27(3):441-458.e10
PubMed 32610040
PubMed Central PMC7758074
DOI 10.1016/j.stem.2020.06.005

Research Projects

Cell Lines