Post-translational modifications of histones and the dynamic DNA methylation cycle are finely regulated by a myriad of chromatin-binding factors and chromatin-modifying enzymes. Epigenetic modifications ensure local changes in the architecture of chromatin, thus controlling the accessibility of the machinery of transcription, replication or DNA repair to the chromatin. Over the past decade, the nutrient-sensor enzyme-GlcNAc transferase (OGT) has emerged as a modulator of chromatin remodeling. In mammals, OGT acts either directly through dynamic and reversible O-GlcNAcylation of histones and chromatin effectors, or in an indirect manner through its recruitment into chromatin-bound multiprotein complexes. In particular, there is an increasing amount of evidence of a cross-talk between OGT and the DNA dioxygenase ten-eleven translocation proteins that catalyze active DNA demethylation. Conversely, the stability of OGT itself can be controlled by the histone lysine-specific demethylase 2 (LSD2). Finally, a few studies have explored the role of -GlcNAcase (OGA) in chromatin remodeling. In this review, we summarize the recent findings on the link between OGT, OGA and chromatin regulators in mammalian cellular models, and discuss their relevance in physiological and pathological conditions.

O-GlcNAcylation (O-linked beta-N-acetylglucosaminylation) is a widespread PTM confined within the nuclear, the cytosolic, and the mitochondrial compartments of eukaryotes. Recently, O-GlcNAcylation has been also detected in the close vicinity of plasma membranes particularly in lipid microdomains. The detection of this PTM can be easily done if appropriate controls and precautions are taken using a wide variety of tools including lectins, antibodies, or click-chemistry-based methods. In contrast, the identification of the proteins bearing O-GlcNAc moieties and the localization of the precise sites of O-GlcNAcylation remain challenging. This is due to the lability of the glycosidic bond between hydroxyl group of serine or threonine and N-acetylglucosamine using conventional fragmentation techniques such as CID. To tentatively overcome this technical limitation, electron-capture dissociation, or electron-transfer dissociation MS/MS are now used. Thanks to these breakthroughs, a large number of O-GlcNAc sites have been identified to date but these methodologies remain far from being used in routine.