O-GlcNAc and the epigenetic regulation of gene expression

Abstract

O-GlcNAcylation is an abundant nutrient-driven modification linked to cellular signaling and regulation of gene expression. Utilizing precursors derived from metabolic flux, O-GlcNAc functions as a homeostatic regulator. The enzymes of O-GlcNAc cycling, OGT and O-GlcNAcase, act in mitochondria, the cytoplasm, and the nucleus in association with epigenetic "writers" and "erasers" of the histone code. Both O-GlcNAc and O-phosphate modify repeats within the RNA polymerase II C-terminal domain (CTD). By communicating with the histone and CTD codes, O-GlcNAc cycling provides a link between cellular metabolic status and the epigenetic machinery. Thus, O-GlcNAcylation is poised to influence trans-generational epigenetic inheritance.

Keywords: Epigenetics; Glycobiology; Histones; O-GlcNAc; O-GlcNAcylation; Polycomb; RNA Polymerase II; Signaling; Transcription.

FIGURE 1.

The central role of UDP-GlcNAc in glycoconjugate synthesis in the endomembrane system and O-GlcNAc-dependent signaling. A, UDP-GlcNAc acts in the assembly of secreted and membrane glycoconjugates and is required for the synthesis of O-GlcNAc in the cytoplasm and nucleus. O-GlcNAc has been implicated in diverse processes as indicated by the arrows. These processes include metabolism, growth, apoptosis, the cell cycle, transcription, translation, the circadian clock, and the establishment of molecular memory in neurons. B, the role of hexosamine synthesis in mediating communication between the mitochondrion and nucleus. Metabolic precursors required for UDP-GlcNAc synthesis, glucose, acetyl-CoA, glutamine, uridine, and ATP are generated by the coordinated activities of cytoplasmic and mitochondrial enzyme complexes. The mitochondrion is the site of fatty acid oxidation to produce acetyl-CoA and the tricarboxylic acid (TCA) cycle utilizing glucose-derived precursors for ATP production. Glutamine is utilized by the action of glutaminase to generate mitochondrial glutamate for entry into the TCA cycle. These interconnected metabolites communicate to the epigenetic machinery by providing precursors for epigenetic modifications including O-GlcNAc addition and histone acetylation. O-GlcNAc addition is mediated by a mitochondrial variant (mOGT), a shorter isoform (sOGT), and the nuclear/cytoplasmic ncOGT. The sOGT variant is present in both cytoplasm and nucleus, although for illustrative purposes, it is shown only the cytoplasm. P indicates phosphorylated residues.

FIGURE 2.

O-GlcNAcylation as an integrator of metabolic flux in response to environmental perturbations. Nutrients, stress, pathogenesis, or other environmental cues such as circadian rhythms are tied to fluctuations in key intermediate metabolites (Δ Metabolites). These include such key intermediates as acetyl-CoA, NADH/NAD, ATP, FAD, α-ketoglutarate, AdoMet (SAM), and UDP-GlcNAc terminating in O-GlcNAc. Enzymes involved in the addition and removal of post-translational modifications maintain homeostasis by responding to these fluctuating metabolite pools by modifying effector molecules that may include cytosine methylation of DNA, histone modifications, transcription factor modifications, and modification of RNA polymerase II. O-GlcNAc cycling provides a central node in these complex homeostatic interactions (adapted from Ref. 49). DNMTs, DNA methyltransferases; lysine MT, lysine methyltransferase; HATS, histone acetyltransferases.

FIGURE 3.

Schematic representation of some CTD post-translational modifications. A, the YSPTSPS CTD consensus repeat is depicted along with the positions of O-GlcNAcylated (G) and phosphorylated residues (P). In addition, some of the proteins that interact with various combinations of the phosphorylated residues are shown. This is not an all-inclusive depiction; other associated factors including capping enzyme and splicing and polyadenylation factors. The reader is referred to several excellent reviews for a thorough discussion of the CTD modifications (72–74). B, the methylation of arginine in CTD repeat 31 (by CARM1 (89)). C, one of eight lysine residues that are acetylated.

FIGURE 4.

Integration of the CTD, histone tails, and the hexosamine biosynthetic pathway. The figure illustrates the numerous connections between nutrient inputs and the CTD, histones, and HSP. Firstly, levels of ACoA, glucose, glutamine, and uridine, as metabolic precursors, may impact synthesis of UDP-GlcNAc by the HBP, which in turn is manifested on the levels of O-GlcNAcylation of the CTD. Additionally, ACoA and AdoMet (SAM) levels likely affect the levels of methylation and acetylation of both the CTD and the histone tails, whereas UDP-GlcNAc levels may be reflected in histone H4 O-GlcNAcylation (53). Of course, any perturbation of glucose and glycogen levels possibly impinges on the extent of CTD phosphorylation (P). Finally, the differing CTD modification states then likely affect, for example, the extent of H3K4 methylation via recruitment of histone methyltransferases (HMTs) to phosphorylated CTD (PCTD) residues. These points illustrate the interconnectivity between RNA pol II, histone tails and their epigenetics, and the HBP and other nutrient sources. pY1, phospho-Tyr-1; pS1, phospho-Ser-2; pT4, phospho-Thr-4; pS5, phospho-Ser-5; pS7, phospho-Ser-7.