© 2019 Butler et al. O-GlcNAcylation of serine/threonine residues on target proteins occurs dynamically in postmitotic neurons of the hippocampus and may serve to control both the stability and activity of target proteins. Remarkably, the addition and removal of the O-GlcNAc posttranslational modifications are catalyzed by a pair of enzymes, the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). More than thousands of proteins are modified by O-GlcNAcylation including epigenetic modifying enzymes. A critical target of OGT is the polycomb repressive complex 2 (PRC2) containing the histone lysine methyltransferase EZH2 that mediates trimethylation of lysine 27 on histone H3 (H3K27me3). However, whether OGT and PRC2 activity in the hippocampus couple to regulate gene transcription mechanisms during memory consolidation remains unknown. Here, we found increases in OGT expression and global O-GlcNAcylation levels in dorsal area CA1 of the hippocampus during memory consolidation. Additionally, we observed that OGT exerts control over epigenetic regulation via EZH2-H3K27me3 during memory consolidation. Blocking O-GlcNAc signaling via RNAi within dorsal area CA1 led to the global and site-specific loss of activity-dependent epigenetic plasticity at genes regulated by H3K27me3 and impairment of hippocampus-dependent memory. Together, these findings illustrate a unique epigenetic role of OGT via regulation of histone methylation mediated by EZH2 during memory consolidation of fear conditioned memories.