Generation of a synthetic GlcNAcylated nucleosome reveals regulation of stability by H2A-Thr101 GlcNAcylation

O- GlcNAcylation is a newly discovered histone modification implicated in transcriptional regulation, but no structural information on the physical effect of GlcNAcylation on chromatin exists. Here, we generate synthetic, pure GlcNAcylated histones and nucleosomes and reveal that GlcNAcylation can modulate structure through direct destabilization of H2A/H2B dimers in the nucleosome, thus promoting an ‘open’ chromatin state. The results suggest that a plausible molecular basis for one role of histone O -GlcNAcylation in epigenetic regulation is to lower the barrier for RNA polymerase passage and hence increase transcription. Post-translational modification of histones has been implicated in gene regulation. Here, Lercher et al. generate synthetic GlcNAcylated histone 2A and nucleosomes and show that this modification can cause nucleosome destabilization, suggesting histone 2A O -GlcNAcylation may promote an open chromatin state and increase transcription.