**Background:** Diet profoundly influences brain physiology and behavior, but the molecular mechanisms by which metabolic information is translated into neural activity changes remain poorly understood. The enzyme O-GlcNAc Transferase (OGT) uses UDP-GlcNAc from the Hexosamine Biosynthesis Pathway to modify proteins and is thought to function as a nutrigenomic sensor. Previous work in Drosophila showed that a high-sugar diet (SD, 30% sucrose) reduces sweet-taste responses and that OGT in sweet-taste neurons is required for this plasticity. This study investigates how OGT, the epigenetic silencer PRC2.1, and the activity-dependent ERK/Stripe pathway integrate nutritional and activity signals at the chromatin level to drive sensory adaptations.
**Methods:** The authors used Targeted Dam-ID (TaDA) to measure OGT chromatin occupancy and CaTaDA to assess chromatin accessibility specifically in Gr5a+ sweet-taste neurons of Drosophila. Translating mRNA Affinity Purification (TRAP) was used to profile gene expression changes in these neurons. Behavioral taste responses were measured using the Proboscis Extension Response (PER) assay, and neural responses were recorded via extracellular tip recording from L-type sensilla. Genetic manipulations included RNAi knockdown, overexpression, and mutant alleles of OGT, Pcl (PRC2.1 recruiter), Stripe (Sr, the Drosophila EGR2/Krox20 homolog), and rolled (rl, the Drosophila ERK homolog). Pharmacological inhibitors included OSMI-1 (OGT inhibitor, 10 μM), EED226/EEDi (PRC2 inhibitor, 8 μM), and Trametinib (ERK inhibitor, 15.6 μM).
**Key Results:** OGT was found to decorate chromatin at introns (51%) and TSSs/promoters (30%), enriched in transcriptionally active 'yellow' euchromatin and 'blue' Polycomb heterochromatin. At loci co-occupied by OGT and PRC2.1 (162 shared intervals), chromatin accessibility decreased markedly (~50%) on SD compared to CD, a change threefold higher than at OGT-only loci. This diet-dependent decrease in accessibility was entirely blocked by OSMI-1 treatment, though PRC2.1 occupancy was unaffected. OGT catalytic activity was required for taste plasticity: OGT knockdown, protein null (OGT^1^), and catalytically dead (OGT^K872M^) mutants all prevented the SD-induced decrease in PER, while OGT overexpression on CD mimicked the SD effect. OSMI-1 blocked both the effects of OGT overexpression and the SD-induced taste decrease. Genetic epistasis showed that Pcl^c429^ mutations blocked OGT overexpression effects, and PRC2 inhibition (EEDi) restored normal taste responses in OGT-overexpressing flies. OSMI treatment reverted or restored 52% of SD/CD differentially expressed genes, with most also affected by Pcl^c429^ mutations. Cis-regulatory motif analysis revealed enrichment for the activity-dependent transcription factor Stripe (Sr/EGR2) at OGT×PRC2.1 loci, particularly in the 500 bp window preceding the TSS. Overexpression of constitutively active rl/ERK (rl^Sem^) decreased neural and behavioral responses to sucrose, an effect blocked by OSMI-1. Trametinib (ERK inhibitor) prevented both the SD-induced decrease in neural responses (CD vs. SD: p=0.0001; Trametinib CD vs. SD: p=0.486) and behavioral responses (main effect of diet: vehicle p<0.0001, Trametinib p=0.4701).
**Clinical Implications:** This study provides a mechanistic framework for how dietary sugar alters neural function through nutrigenomic signaling, demonstrating that metabolic and activity-dependent signals are integrated at the chromatin level to drive sensory plasticity. The identification of OGT, PRC2.1, and ERK/EGR2 as key components of this pathway offers potential molecular targets for understanding how diet influences brain function in metabolic and neurological conditions. While conducted in Drosophila, the conservation of OGT, PRC2, and ERK/EGR2 pathways across species suggests these mechanisms may have relevance for human conditions where diet affects neural function, including obesity, diabetes, and neurodegenerative diseases.