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

Research output: Contribution to journalJournal articlepeer-review

  • Le Tran Phuc Khoa
  • Yao-Chang Tsan
  • Fengbiao Mao
  • Daniel M Kremer
  • Peter Sajjakulnukit
  • Li Zhang
  • Bo Zhou
  • Xin Tong
  • Natarajan V Bhanu
  • Choudhary, Chuna Ram
  • Benjamin A Garcia
  • Lei Yin
  • Gary D Smith
  • Thomas L Saunders
  • Stephanie L Bielas
  • Costas A Lyssiotis
  • Yali Dou

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.

Original languageEnglish
JournalCell Stem Cell
Volume27
Issue number3
Pages (from-to)441-458.e10
Number of pages29
ISSN1934-5909
DOIs
Publication statusPublished - 2020

ID: 244995365