EPIGENETIC REPROGRAMMING BY FLAV‑27 RESTORES FMR1-DEPENDENT CHROMATIN LANDSCAPES IN A MOUSE MODEL OF AUTISM

Epigenetic regulation of chromatin accessibility in FMR1-linked autism remains incompletely understood. In this research, we combined hippocampal ATAC-seq data from Fmr1 knockout (KO), FLAV-27-treated Fmr1 KO, and WT mice with behavioral and transcriptomic analyses to examine how FLAV-27 affects regulatory structures and synaptic function. Fmr1 KO mice showed widespread changes in chromatin accessibility, mainly in distal intergenic and intronic regions. These changes included increased openness at loci related to cytoskeletal remodeling, cell adhesion, basal transcription factors, and SWI/SNF chromatin remodelers, as well as decreased accessibility at genes involved in receptor signaling, cell-cycle, and ubiquitin regulation—indicating disrupted cis-regulatory modules and transcriptional balance. FLAV-27 specifically remodeled the chromatin landscape of KO mice, increasing accessibility at regions linked to inhibitory synapse formation, GABAergic signaling, chloride transport, and neuroactive pathways. It also decreased accessibility at elements involved in eIF2-mediated stress responses, ER stress, immune defenses, autophagy, and inflammation, suggesting a restoration of the excitation–inhibition balance and reduced stress signaling. Comparing FLAV-27 to WT mice showed decreased accessibility at genes such as Arhgap6, Marchf5, Ppm1h, and Erdr1x. Gained peaks were associated with cell adhesion, extracellular matrix, and axon guidance, while lost peaks were associated with mitophagy and AMPK signaling—indicating subtle shifts in cytoskeletal, matrix, and energy pathways. Overall, these findings reveal that FLAV-27 acts as a specific epigenetic modulator, reprogramming chromatin accessibility disrupted by FMR1 deficiency. It boosts inhibitory and synaptic networks while reducing stress and immune responses, highlighting its potential to correct gene regulation issues in Fmr1-related autism models.