O-GlcNAcylation and 5-methylcytosine oxidation: an unexpected association between OGT and TETs

Abstract

Three recent studies, including one in this issue of Molecular Cell, document unexpected physical and functional interactions between two unrelated enzymes: OGT, which transfers O-GlcNAc to serine/threonine residues of numerous cellular proteins, and TET-family dioxygenases, which successively oxidize 5-methylcytosine in DNA.

Figure 1. TET-OGT Complexes Modulate Chromatin Conformation and Gene Expression at CpG-Rich TSSs in Mouse ESCs

(A) TET proteins catalyze sequential oxidation of 5mC to 5hmC, 5fC, and 5caC, potentially facilitating DNA demethylation. Ineffective recognition of the oxidized forms of 5mC by the maintenance DNA methyltransferase Dnmt1 could facilitate passive DNA demethylation, whereas TDG-dependent excision of 5fC and 5caC could mediate active DNA demethylation. (B) OGT and OGA act as terminal effectors of the hexosamine biosynthesis pathway by modulating O-GlcNAcylation of serine/threonine residues on proteins. (C) Left panel: In mESCs, Tet1-Ogt complexes are predominantly recruited to CpG-rich TSSs that correspond to transcriptionally active genes. Tet1 and Tet2 are depicted as tightly and loosely bound to chromatin, respectively; both interact with Ogt. Hcfc1 binds Ogt directly, but whether it is part of the OGT-TET complex is not clear. Middle panel: Approximately 70% of the sites that corecruit Tet1 and Ogt also recruit mSin3a, which cooperates with Tet1 to maintain transcriptional repression. Right panel: TET1 also binds many sites that are not co-occupied by OGT, many of them potentially distal cis-regulatory regions (e.g., enhancers). The TET1 partners at these sites are unknown but could include transcription factors and other transcriptional regulators (Stadler et al., 2011).