title: Glutamine Metabolism Regulates the Pluripotency Transcription Factor OCT4.
abstract: 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 OCT4(lo) 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.
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA. Electronic address: gmarsboo@uic.edu.
authors.forename: Glenn
authors.initials: G
authors.lastname: Marsboom
authors.affiliation: Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
authors.forename: Guo-Fang
authors.initials: GF
authors.lastname: Zhang
authors.affiliation: Division of Cardiology, Department of Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pohl-Avila
authors.affiliation: Division of Cardiology, Department of Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA; Department of Pathology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Hojin
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Hao
authors.affiliation: Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Henri
authors.initials: H
authors.lastname: Brunengraber
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA; Division of Cardiology, Department of Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA. Electronic address: jalees@uic.edu.
authors.forename: Jalees
authors.initials: J
authors.lastname: Rehman
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D003545:Cysteine / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D042783:Endothelial Cells / Q000502:physiology; D005973:Glutamine / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000502:physiology*; D006801:Humans; D018919:Neovascularization, Physiologic; D050814:Octamer Transcription Factor-3 / Q000737:chemistry / Q000502:physiology*; D011485:Protein Binding; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D017382:Reactive Oxygen Species; D005973:Glutamine; D004247:DNA; D005978:Glutathione; D003545:Cysteine