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

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

doi:10.1016/j.stem.2020.06.005

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. Epub 2020 Jun 30.

Authors

Le Tran Phuc Khoa¹, Yao-Chang Tsan², Fengbiao Mao¹, Daniel M Kremer³, Peter Sajjakulnukit³, Li Zhang³, Bo Zhou¹, Xin Tong³, Natarajan V Bhanu⁴, Chunaram Choudhary⁵, Benjamin A Garcia⁴, Lei Yin³, Gary D Smith⁶, Thomas L Saunders⁷, Stephanie L Bielas², Costas A Lyssiotis³, Yali Dou⁸

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].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation
Cell Division
Embryonic Stem Cells*
Fatty Acids
Histone Acetyltransferases* / genetics
Humans

Substances

Fatty Acids
Histone Acetyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding