Chromatin Accessibility Profiling of the Canine Brain Reveals Regulatory Programs Associated With Dog‐Wolf Divergence and Human Psychiatric Risk
Biao Deng, Junze Wu, Ye Liu, Xuan Li, Yuanfang Xu, Rongjie Duan, Yibo Tong, Jinsheng Xu, Mengyang Ni, Zijie Scott Zhang, Dan Xue, Bowen Zhou, Yanhu Liu, Rui Cheng, Yuedong Zhang, Ya‐Ping ZhangABSTRACT
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.