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

  • Cell Stem Cell. 2020 Sep 3;27(3):441-458.e10. doi: 10.1016/j.stem.2020.06.005.
Le Tran Phuc Khoa  1 ,  Yao-Chang Tsan  2 ,  Fengbiao Mao  1 ,  Daniel M Kremer  3 ,  Peter Sajjakulnukit  3 ,  Li Zhang  3 ,  Bo Zhou  1 ,  Xin Tong  3 ,  Natarajan V Bhanu  4 ,  Chunaram Choudhary  5 ,  Benjamin A Garcia  4 ,  Lei Yin  3 ,  Gary D Smith  6 ,  Thomas L Saunders  7 ,  Stephanie L Bielas  2 ,  Costas A Lyssiotis  3 ,  Yali Dou  8
Affiliations
  • 1. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • 2. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • 3. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • 4. Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5. Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
  • 6. Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 7. Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • 8. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: [email protected].
PMID: 32610040 DOI: 10.1016/j.stem.2020.06.005
Abstract

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.

Keywords
FAO; MOF; cell fate decision; embryo development; epigenetics; quiescence; self-renewal; stem cell metabolism.
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