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

• DOI: 10.1016/j.stem.2020.06.005
• Publication Date: 2020-06-30T18:19:23Z
• Authors: Le Tran Phuc Khoa; Yao-Chang Tsan; Fengbiao Mao; Daniel M. Kremer; Peter Sajjakulnukit; Li Zhang; Bo Zhou; Xin Tong; Natarajan V. Bhanu; Chunaram Choudhary; Benjamin A. Garcia; Lei Yin; Gary D. Smith; Thomas L. Saunders; Stephanie L. Bielas; Costas A. Lyssiotis; Yali Dou
• Keywords: 0301 basic medicine; 03 medical and health sciences; Fatty Acids; Humans; Cell Differentiation; Cell Division; Embryonic Stem Cells; Histone Acetyltransferases

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.