The basal ganglia play essential roles in motor control, emotion, learning and reward processing. Their dysfunction contributes to many neurological and psychiatric disorders. However, the gene regulatory programs defining basal ganglia cell-type identity and function remain poorly understood, limiting interpretation of disease-associated non-coding variants. Here, we present the first single-cell multiome atlas of histone modifications and transcriptomes across eight basal ganglia regions from neurotypical adult human donors. Joint profiling reveals cell-type-specific deployment of active and repressive cis-regulatory elements and gene regulatory networks, and suggests a combinatorial homeobox transcription factor code underlying cell identity. Integration with matched spatial transcriptomic MERFISH data uncovers regional heterogeneity of epigenomic landscapes. Comparative analysis between human and mouse medium spiny neurons uncovers conservation of core gene regulatory features. This atlas interprets non-coding risk variants of neuropsychiatric disorders and supports the development of a deep learning model to predict gene regulation and functional effects of disease-associated variants.
HIGHLIGHTS
Joint single-cell profiling of transcriptomes and three histone modifications across eight human basal ganglia regions characterizes active and repressive chromatin states at cell-type resolution.
Cell-type-specific gene regulatory programs decode combinatorial homeobox TF grammar governing the identity and diversification of basal ganglia neurons.
Intergrative analyses link noncoding neuropsychiatric risk variants to specific cell types, regulatory elements, and candidate target genes.
A sequence-to-function deep-learning model predicts gene regulation from DNA sequence and prioritizes functional disease-associated variants.
