Neuron-specific WDR5 epigenetically upregulates ARID5B to impair GABAergic synaptic transmission and promotes epileptogenesis

<b>Rationale:</b> Temporal lobe epilepsy (TLE) is a prevalent, drug-resistant neurological disorder that causes severe disability, highlighting the need to identify novel therapeutic targets. Emerging evidence reveals widespread transcriptional dysregulation during epileptogenesis, in which multiple dysregulated genes functionally contribute to disease progression. However, the epigenetic basis of these transcriptomic changes remains poorly characterized. <b>Methods:</b> We established experimental epilepsy models and systematically investigated the remodeling of major histone methylation modifications during epileptogenesis using integrated low-throughput molecular assays and epigenomic profiling. Through pharmacological and genetic interventions, combined with synchronized video-EEG monitoring, whole-cell patch-clamp recordings, multi-omics analyses, and <i>in vivo</i>/<i>ex vivo</i> molecular biology approaches, we mechanistically dissected the pathological role of elevated histone H3 lysine 4 trimethylation (H3K4me3) in epileptogenesis. <b>Results:</b> We demonstrated the dynamic increase in H3K4me3, an epigenetic marker of transcriptional activation, during TLE development. Both pharmacological inhibition of the WD repeat-containing protein 5 (WDR5)-lysine methyltransferase 2 (KMT2) methyltransferase complex and neuron-specific WDR5 knockdown consistently conferred anti-epileptogenic effects. Mechanistically, integrated ChIP-seq and RNA-seq analyses identified AT-rich interactive domain-containing protein 5B (ARID5B) as a key WDR5-targeted effector in hippocampal neurons. WDR5 enhances H3K4me3 deposition at the <i>Arid5b</i> promoter to drive its transcriptional upregulation. The upregulated ARID5B protein subsequently represses γ-aminobutyric acid type A receptor (GABA_AR) subunit expression, impairing inhibitory synaptic transmission and facilitating epileptogenesis. In addition, the WDR5-H3K4me3 axis may directly or indirectly regulate genes involved in glutamatergic synaptic transmission. <b>Conclusions:</b> The neuronal WDR5-H3K4me3 axis is an important epigenetic driver in epileptogenesis, providing both mechanistic insights and promising therapeutic targets for early intervention.