TET2 promotes histone O-GlcNAcylation during gene transcription

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SummaryTET enzymes including TET1, 2 and 3 convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC)1 and regulate gene transcription2-5. However, this molecular mechanism by which TET family enzymes regulate gene transcription remains elusive5-6. Here, using protein affinity purification, we searched for functional partners of TET proteins, and found that TET2 and TET3 associate with OGT, an enzyme that by itself catalyzes O-GlcNAcylation in vivo7-8. TET2 directly interacts with OGT, which is important for the chromatin association of OGT in vivo. Although this specific interaction does not regulate the enzymatic activity of TET2, it facilitates OGT-dependent histone O-GlcNAcylation. Moreover, OGT associates with TET2 at transcription starting sites (TSS). Down-regulation of TET2 reduces the amount of H2B S112 GlcNAc marks in vivo, which are associated with gene transcription regulation. Taken together, these results reveal a TET2-dependent O-GlcNAcylation of chromatin. The double epigenetic modifications on both DNA and histones by TET2 and OGT coordinate together for the gene transcription regulation.