Abstract
Embryonic and adult stem cells possess the capability of self-renewal and lineage-specific differentiation. The intricate balance between self-renewal and differentiation is governed by developmental signals and cell-type-specific gene regulatory mechanisms. A perturbed intra/extracellular environment during lineage specification could affect stem cell fate decisions resulting in pathology. Growing evidence demonstrates that metabolic pathways govern epigenetic regulation of gene expression during stem cell fate commitment through the utilization of metabolic intermediates or end products of metabolic pathways as substrates for enzymatic histone/DNA modifications. UDP-GlcNAc is one such metabolite that acts as a substrate for enzymatic mono-glycosylation of various nuclear, cytosolic, and mitochondrial proteins on serine/threonine amino acid residues, a process termed protein O-GlcNAcylation. The levels of GlcNAc inside the cells depend on the nutrient availability, especially glucose. Thus, this metabolic sensor could modulate gene expression through O-GlcNAc modification of histones or other proteins in response to metabolic fluctuations. Herein, we review evidence demonstrating how stem cells couple metabolic inputs to gene regulatory pathways through O-GlcNAc-mediated epigenetic/transcriptional regulatory mechanisms to govern self-renewal and lineage-specific differentiation programs. This review will serve as a primer for researchers seeking to better understand how O-GlcNAc influences stemness and may catalyze the discovery of new stem-cell-based therapeutic approaches.
Highlights
Glucose serves as a signaling molecule to govern the process of cell proliferation and differentiation [1, 5]
By providing metabolites that act as cofactors for histone and DNA modification enzymes and substrates for posttranslational modifications (PTMs) of transcription factors/epigenetic regulators, cellular metabolism could play a critical role in the regulation of the epigenome [11, 13]
We will discuss the results of recent studies conducted in embryonic stem cells (ESCs) as well as adult stem cells combined with data from animal models on the effects of global O-GlcNAc levels on stem cell fate, the role of O-GlcNAcylation of key transcription factors in stem cell pluripotency and differentiation, and the role of other O-GlcNAc-mediated gene regulatory mechanisms
Summary
Embryonic and adult stem cells possess the capability of selfrenewal and lineage-specific differentiation. We will discuss the results of recent studies conducted in ESCs as well as adult stem cells combined with data from animal models on the effects of global O-GlcNAc levels on stem cell fate, the role of O-GlcNAcylation of key transcription factors in stem cell pluripotency and differentiation, and the role of other O-GlcNAc-mediated gene regulatory mechanisms These discussions will provide up-to-date information on protein O-GlcNAcylation in stem cells and development but may guide future studies with a focus on protein O-GlcNAcylation on pathological conditions, which deal with stem cell functions and metabolic perturbations such as the effects of diabetic pregnancy on the fetus. Since S248 lies in the transactivation domain of SOX2, it was not surprising that mutant form of
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