Stem cell fate determination through protein O-GlcNAcylation

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 which 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.

The glycobiological landscape of breast cancer: insights into galectins and O-GlcNAc homeostasis-related genes

“…These gene pairs could be potential diagnostic markers for breast cancer, although the functional meaning and molecular mechanisms behind of these correlations remain to be determined. Overall, given the dysregulated O-GlcNAc homeostasis in cancer tissues [20,21,29] and sensitivity of galectins and stemness-related transcription factors to O-GlcNAcylation [31,46,[56][57][58][59], our results rationalize that this type of functional associations between the genes of the glycobiological landscape deserves further investigations focusing on O-GlcNAc/galectin signaling in appropriate cancer models.…”

O‐GlcNAcylation drives calcium signaling toward osteoblast differentiation: A bioinformatics‐oriented study

“…These studies also showed that O-GlcNAcylation occurs in a cell lineage-specific manner during cell differentiation. [12][13][14][15][16] The levels of glucose uptake and utilization are relatively high in pluripotent stem cells, and their levels change as the cells begin to differentiate. 15 Changes in glucose uptake and utilization levels also result in various global O-GlcNAc levels during differentiation.…”

“…[12][13][14][15][16] The levels of glucose uptake and utilization are relatively high in pluripotent stem cells, and their levels change as the cells begin to differentiate. 15 Changes in glucose uptake and utilization levels also result in various global O-GlcNAc levels during differentiation. 15 However, investigation on the changes and distribution of global O-GlcNAcylated proteins during osteoblast differentiation are not very detailed.…”

Progenitor/Stem Cells in Vascular Remodeling during Pulmonary Arterial Hypertension

“…This transition is characterized by a decrease in SM-MHC expression (terminal marker of differentiation) and the expression of the pluripotential factor Kruppel-Like Factor 4 (KLF4) induced by the activation of PDGFRβ following the increase in pulmonary EC-derived PDGF-B production. Increased KLF4 expressing PDGFRβ + /KLF4 + SMC were found in remodeling pulmonary arteries in the CH mouse model as well as in pulmonary arterioles of PH and PAH patients with a strong correlation with proliferative SMCs [44][45][46].…”

“…Another important pathway linked to glucose metabolism is the O-GlcNAcylation, i.e., the glycosylation of intracellular proteins with N-acetyl-d-glucosamine, which was found to be increased both in iPAH patients and in PH models [154]. This dynamic posttranslational modification leads to changes in protein function, trafficking, and localization and regulates stem cell self-renewal, pluripotency, and differentiation, in part, via epigenetic regulations (for review, see [46]). In particular, O-GlcNAcylation stabilizes HIF-1α [155], SMAD4, a major regulator of TGF-β and BMP signaling pathways [156], or the EndMT regulator SNAIL1 [157].…”