You are what you eat

Abstract

Purpose of review The O-linked N-acetylglucosamine (O-GlcNAc) modification is both responsive to nutrient availability and capable of altering intracellular cellular signaling. We summarize data defining a role for O-GlcNAcylation in metabolic homeostasis and epigenetic regulation of development in the intrauterine environment. Recent Findings O-GlcNAc Transferase (OGT) catalyzes nutrient-driven O-GlcNAc addition and is subject to random X-inactivation. OGT plays key roles in growth factor signaling, stem cell biology, epigenetics, and possibly imprinting. The O-GlcNAcase, which removes O-GlcNAc is subject to tight regulation by higher order chromatin structure. O-GlcNAc cycling plays an important role in the intrauterine environment where OGT expression is an important biomarker of placental stress. Summary Regulation of O-GlcNAc cycling by X-inactivation, epigenetic regulation, and nutrient-driven processes make it an ideal candidate for a nutrient-dependent epigenetic regulator of human disease. In addition, O-GlcNAc cycling influences chromatin modifiers critical to the regulation and timing of normal development including the polycomb repression complex (PRC2) and the TET proteins mediating DNA methyl cytosine demethylation. The pathway also impacts the Hypothalamic-Pituitary-Adrenal Axis critical to intrauterine programming influencing disease susceptibility in later life.

Silencing the Nucleocytoplasmic O-GlcNAc Transferase Reduces Proliferation, Adhesion, and Migration of Cancer and Fetal Human Colon Cell Lines

“…Moreover, a deregulation in the O -GlcNAcylation cycling is involved in the etiology of diverse pathologies, such as type-2 diabetes, Alzheimer’s, and cancers ( 6 ). Intriguingly, due to the correlation between UDP-GlcNAc, O -GlcNAcylation, and nutrients availability, diseases associated with unhealthy diet and metabolic disorders may be tightly linked to O -GlcNAcylation imbalance ( 28 ). It is, therefore, crucial to better understand through which metabolic mechanisms lifestyles negatively impact human health.…”

Redox biology and the interface between bioenergetics, autophagy and circadian control of metabolism

“…For changes in protein methylation, part of the mechanism of action is through the post-translational nitrosyliron complex formation in the catalytic pocket of the demethylase lysine demethylase 3A (KDM3A) [59]. Another important post-translational modification integrating metabolic redox signaling to epigenetic pathways is protein O-GlcNAcylation that will be discussed in the next section [60-62]. …”

“…In this respect the post-translational modification of proteins by the attachment of β-N-acetylglucosamine on serine and threonine residues via an O-linkage (O-GlcNAc) is achieving particular prominence because of its intimate relationship with glycolysis, response to oxidative stress and as a nexus linking nutrient signaling to gene expression [60-62, 69, 70]. In contrast to typical glycosylation, O-GlcNAcylation is a dynamic and reversible modification, regulated by O-GlcNAc transferase (OGT), a glycosyl transferase that uses UDP-GlcNAc to catalyze the attachment of O-GlcNAc to proteins and O-GlcNAcase, a hexosaminidase, which catalyzes its removal.…”

O-GlcNAc homeostasis contributes to cell fate decisions during hematopoiesis

“…OGT and OGA interact with the GATA-1-FOG-1-Mi2␤ (NuRD) repressor complex at the A ␥-globin promoter, and O-GlcNAcylation of the NuRD chromatin-remodeling complex is necessary for GATA-1-FOG-1-Mi2␤ repressor formation (20). Other studies have demonstrated that O-GlcNAc cycling on chromatin modifiers is critical for modulation of gene transcription and normal development (33,34). Thus, O-GlcNAc might regulate hematopoietic cell differentiation and maturation.…”