Integrated ATAC-seq and RNA-seq analysis identifies Grid2 and Reln as potential regulatory genes in migraine pathophysiology.

BACKGROUND: Migraine pathophysiology involves epigenetic mechanisms, but key molecular regulators remain poorly defined. This study aimed to elucidate these mechanisms using a comprehensive multi-omics approach. METHODS: We established a nitroglycerin (NTG)-induced migraine-like mouse model. Sensory hypersensitivity was assessed via behavioral tests, and neuronal activation was evaluated by immunofluorescence staining for c-Fos in the trigeminal nucleus caudalis. Integrated transcriptomic profiling (RNA-seq) and epigenomic analysis (ATAC-seq) were performed, followed by differential expression and accessibility analyses, functional enrichment, multi-omics integration, protein-protein interaction network construction, and in silico drug prediction using tools like Enrichr. RESULTS: NTG treatment induced significant sensory hypersensitivity, with reduced mechanical thresholds and increased c-Fos expression. RNA-seq identified 140 significantly upregulated genes, while ATAC-seq revealed 282 significantly open differentially accessible chromatin regions (DACRs). Multi-omics integration pinpointed Grid2 and Reln as central effectors, enriched in synaptic pathways. Functional analyses highlighted roles in synaptic signaling, and network analysis identified key transcription factors (e.g., Etv1, Neurod1) as hubs. Drug prediction prioritized glutamate receptor antagonists as potential therapeutics. CONCLUSION: This study identifies Grid2 and Reln as plausible regulators in migraine pathophysiology, with implications for synaptic mechanisms. The findings provide novel insights into migraine etiology and highlight promising targets for therapeutic intervention. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10194-025-02228-4.