2. Academic Validation
  3. Histone Acetyltransferase MOF Blocks Acquisition of Quiescence in Ground-State ESCs through Activating Fatty Acid Oxidation

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

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: yalidou@usc.edu.
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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