Glutamine Metabolism Regulates the Pluripotency Transcription Factor OCT4
Glenn Marsboom,
Guo-Fang Zhang,
Nicole Pohl-Avila,
Yanmin Zhang,
Yang Yuan,
Hojin Kang,
Bo Hao,
Henri Brunengraber,
Asrar B. Malik,
Jalees Rehman
Affiliations
Glenn Marsboom
Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA
Guo-Fang Zhang
Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA
Nicole Pohl-Avila
Division of Cardiology, Department of Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA
Yanmin Zhang
Division of Cardiology, Department of Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA
Yang Yuan
Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA
Hojin Kang
Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA
Bo Hao
Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA
Henri Brunengraber
Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA
Asrar B. Malik
Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA
Jalees Rehman
Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA
The molecular mechanisms underlying the regulation of pluripotency by cellular metabolism in human embryonic stem cells (hESCs) are not fully understood. We found that high levels of glutamine metabolism are essential to prevent degradation of OCT4, a key transcription factor regulating hESC pluripotency. Glutamine withdrawal depletes the endogenous antioxidant glutathione (GSH), which results in the oxidation of OCT4 cysteine residues required for its DNA binding and enhanced OCT4 degradation. The emergence of the OCT4lo cell population following glutamine withdrawal did not result in greater propensity for cell death. Instead, glutamine withdrawal during vascular differentiation of hESCs generated cells with greater angiogenic capacity, thus indicating that modulating glutamine metabolism enhances the differentiation and functional maturation of cells. These findings demonstrate that the pluripotency transcription factor OCT4 can serve as a metabolic-redox sensor in hESCs and that metabolic cues can act in concert with growth factor signaling to orchestrate stem cell differentiation.
