Chromatin Accessibility Profiling of the Canine Brain Reveals Regulatory Programs Associated With Dog‐Wolf Divergence and Human Psychiatric Risk

The domestic dog has emerged as a valuable model for investigating the biology of social behavior and neuropsychiatric disease, yet a comprehensive map of gene regulatory elements across the canine brain is still lacking. Here, we generated an ATAC-seq atlas spanning seven major brain regions and the pituitary gland from four adult beagle dogs. We identified 251,492 putative cis-regulatory elements (CREs) and found that chromatin accessibility profiles resolve anatomically distinct regions into discrete regulatory modules, including striatal, cortical-associated, hypothalamic/habenular, and pituitary groups. Region-specific accessible elements were enriched predominantly in distal non-coding regions and were associated with distinct transcription factor (TF) programs and biological functions. Integration with dog-wolf genetic differentiation signals identified tissue-specific CREs overlapping highly differentiated genomic regions, including loci linked to neuronal and neuroendocrine pathways. Cross-species integration of human Genome-Wide Association Study data further indicated that canine cortical-associated chromatin features and striatal-enriched chromatin signatures, along with genes linked to such CREs, exhibit enrichment for schizophrenia (SCZ) and bipolar disorder (BD) risk signals. Together, these findings delineate the regional cis-regulatory landscape of the canine brain and support the dog as a translational model for studying the regulatory basis of neuropsychiatric disease.