2. Academic Validation
  3. Chemical Modulation of Protein O-GlcNAcylation via OGT Inhibition Promotes Human Neural Cell Differentiation

Chemical Modulation of Protein O-GlcNAcylation via OGT Inhibition Promotes Human Neural Cell Differentiation

  • ACS Chem Biol. 2017 Aug 18;12(8):2030-2039. doi: 10.1021/acschembio.7b00232.
Lissette M Andres 1,  Ian W Blong 2,  Angela C Evans 3,  Neil G Rumachik 4,  Teppei Yamaguchi 1,  Nam D Pham 5,  Pamela Thompson 3,  Jennifer J Kohler 5,  Carolyn R Bertozzi 4 6
Affiliations

Affiliations

  • 1 Department of Molecular and Cell Biology, University of California , Berkeley, California 94720, United States.
  • 2 Department of Stem Cell Biology and Regenerative Medicine, Stanford University , Stanford, California 94305, United States.
  • 3 Department of Chemistry, University of California , Berkeley, California 94720, United States.
  • 4 Department of Chemistry, Stanford University , Stanford, California 94305, United States.
  • 5 Department of Biochemistry, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States.
  • 6 Howard Hughes Medical Institute , Chevy Chase, Maryland, United States.
PMID: 28541657 DOI: 10.1021/acschembio.7b00232
Abstract

The Enzymes that determine protein O-GlcNAcylation, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), act on key transcriptional and epigenetic regulators, and both are abundantly expressed in the brain. However, little is known about how alterations in O-GlcNAc cycling affect human embryonic stem cell (hESC) neural differentiation. Here, we studied the effects of perturbing O-GlcNAcylation during neural induction of hESCs using the metabolic inhibitor of OGT, peracetylated 5-thio-N-acetylglucosamine (Ac4-5SGlcNAc). Treatment of hESCs with Ac4-5SGlcNAc during induction limited protein O-GlcNAcylation and also caused a dramatic decrease in global levels of UDP-GlcNAc. Concomitantly, a subpopulation of neural progenitor cells (NPCs) acquired an immature neuronal morphology and expressed early neuronal markers such as β-III tubulin (TUJ1) and microtubule associated protein 2 (MAP2), phenotypes that took longer to manifest in the absence of OGT inhibition. These data suggest that chemical inhibition of OGT and perturbation of protein O-GlcNAcylation accelerate the differentiation of hESCs along the neuronal lineage, thus providing further insight into the dynamic molecular mechanisms involved in neuronal development.

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