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  • Review Article
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Bittersweet memories

linking metabolism to epigenetics through O-GlcNAcylation

Nature Reviews Molecular Cell Biology volume 13, pages 312–321 (2012)Cite this article

Subjects

Key Points

  • O-GlcNAcylation is a nutrient-driven post-translational modification, as the levels of O-GlcNAcylation depend on the intracellular concentration of the cytoplasmic nucleotide sugar uridine diphosphate N-acetylglucosamine (UDP-GlcNAc).

  • O-GlcNAc transferase (OGT) catalyses the addition of O-linked β-D-N-acetylglucosamine (O-GlcNAc) to Ser or Thr residues on target substrates, whereas O-GlcNAcase (OGA) catalyses O-GlcNAc removal.

  • OGT and OGA regulate O-GlcNAc cycling in a range of organisms, including Drosophila melanogaster, Caenohabditis elegans and mammals. O-GlcNAc cycling affects signalling, organelle dynamics, the cell cycle and transcription. Emerging evidence suggests that O-GlcNAcylation is a central player in the robust regulatory network of post-translational modifications, which constitute the epigenetic lexicon.

  • OGT and OGA interact with transcriptional regulators such as host cell factor 1 (HCF1), histones, histone modifiers and RNA polymerase II (Pol II). In addition, O-GlcNAcylation regulates the function of the Polycomb group (PcG) and Trithorax group (TrxG) complexes.

  • As it targets several crucial factors that control gene expression and epigenetic control, O-GlcNAcylation may be one of the mechanisms linking nutritional information to disease susceptibility across generations.

Abstract

O-GlcNAcylation, which is a nutrient-sensitive sugar modification, participates in the epigenetic regulation of gene expression. The enzymes involved in O-linked β-D-N-acetylglucosamine (O-GlcNAc) cycling – O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) – target key transcriptional and epigenetic regulators including RNA polymerase II, histones, histone deacetylase complexes and members of the Polycomb and Trithorax groups. Thus, O-GlcNAc cycling may serve as a homeostatic mechanism linking nutrient availability to higher-order chromatin organization. In response to nutrient availability, O-GlcNAcylation is poised to influence X chromosome inactivation and genetic imprinting, as well as embryonic development. The wide range of physiological functions regulated by O-GlcNAc cycling suggests an unexplored nexus between epigenetic regulation in disease and nutrient availability.

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Figure 1: The synthesis of UDP-GlcNAc via the hexosamine biosynthetic pathway is nutrient responsive.
Figure 2: The structure and function of the enzymes of O-GlcNAc cycling.
Figure 3: The enzymes of O-GlcNAc cycling interact with and modify known epigenetic regulators.
Figure 4: The influence of O-GlcNAc cycling on the activity of the PcG and TrxG complexes.

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Acknowledgements

The authors wish to thank P. Wang, M. Bond, T. Fukushige and K. Harwood for helpful discussions. The work was supported by National Institutes of Diabetes and Digestive and Kidney Diseases intramural funds.

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  1. Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA

    John A. Hanover & Dona C. Love

  2. Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Michael W. Krause

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  1. John A. Hanover
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Correspondence to John A. Hanover, Michael W. Krause or Dona C. Love.

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SUPPLEMENTARY INFORMATION

S1 (box)

Glossary

Histone code

The presumptive information content encoded by post-translational modifications of the histone tails. The histone code has been implicated in the regulation of gene expression, with histone acetylation being associated with increased expression and histone methylation with transcriptional repression.

Protein glycosylation

Addition of saccharide residues in glycosidic linkage to amino acid residues of proteins. Typical linkages are amide linkages to Asn (N-glucosylation) and glycosidic linkages to Ser or Thr (O-glycosylation).

Glycosyltransferases

Enzymes that transfer saccharides from sugar nucleotide precursors to target proteins, oligosaccharides and lipids.

Polycomb group

(PcG). A family of proteins that can remodel chromatin and silence genes. This protein family was first discovered in Drosophila melanogaster.

CTD code

The presumptive information content encoded by post-translational modifications of the carboxy-terminal domain (CTD) of RNA polymerase II (Pol II), which contains heptad repeats. CTD modifications, such as phosphorylation and O-GlcNAcylation, are thought to regulate the activity of Pol II.

Hexosamine biosynthetic pathway

(HBP). An offshoot of the glycolytic pathway that normally accounts for 2—5% of glucose flux. The HBP generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) and uridine diphosphate N-acetylgalactosamine (UDP-GalNAc) from Gln, glucose, acetyl-CoA, ATP and uridine.

Tetratricopeptide repeats

(TPRs). Structural motifs that are found in a wide range of proteins. TPRs are composed of 34 amino acids and are involved in intra- and intermolecular interactions.

Sequential-ordered bi-bi kinetics

A kinetic system in which substrates must be bound sequentially and in the proper order to carry out two bimolecular reactions.

TIM-barrel

(Triosephosphate isomerise-barrel). The most frequent and conserved protein fold that comprises eight helices and eight sheets.

MAD—MAX complex

A sequence-specific transcriptional repressor complex consisting of the bHLH-ZIP proteins MAD and MAX. The MAD—MAX complex antagonizes the transcriptional activity of the MYC—MAX complex.

Swi—Snf complex

A chromatin-remodelling complex family that was first identified genetically in yeast as a group of genes required for mating type switching and growth on alternative sugar sources to sucrose. This complex is required for the transcriptional activation of ~7% of the genome.

Ssn6—Tup1 complex

A complex consisting of the yeast proteins Ssn6 (also known as Cyc8) and Tup1. This complex is associated with glucose repression.

Trithorax group

(TrxG). Chromatin regulatory proteins that maintain gene expression, often by antagonizing the Polycomb group proteins.

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Hanover, J., Krause, M. & Love, D. linking metabolism to epigenetics through O-GlcNAcylation. Nat Rev Mol Cell Biol 13, 312–321 (2012). https://doi.org/10.1038/nrm3334

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