Single-Cell Analysis of Chromatin State and Transcriptome in Human Basal Ganglia

The basal ganglia, a collection of interconnected subcortical nuclei, plays a central role in motor control, emotion, and reward processing. Dysfunctions in these circuits contribute to numerous neurological disorders, including Parkinson's disease, Huntington's disease, and various psychiatric diseases. While thousands of genetic variants have been associated with these diseases, most reside in non-coding regions of the genome and remain functionally uncharacterized. These risk variants likely influence disease by perturbing transcriptional regulatory elements in a cell-type-specific manner. However, the lack of comprehensive annotation of the cell-type-specific regulatory elements and their activity has prevented us from gaining a deeper understanding of the roles these non-coding risk variants play in disease pathogenesis. Here, we present a comprehensive joint single-cell atlas of histone modifications and transcriptome across eight basal ganglia regions from seven neurotypical adult human donors, generated by Droplet Paired-Tag. This dataset encompasses ~800,000 cells and covers three histone modifications -- H3K27ac, H3K27me3, and H3K9me3. We identified 1,787 cell populations, 60 distinct cell groups, and annotated chromatin states for approximately 60% of the genome for each cell type. Our analysis revealed 1,430,938 active and repressive putative regulatory elements, many of which exhibit evolutionary conservation and consistent chromatin signatures in the mouse brain, underscoring their functional significance. We also investigated the distinct regulatory programs underlying the D1 and D2 subtypes of medium spiny neurons, which have divergent roles in movement regulation. To map regulatory activity in anatomical context, we also generated a spatial transcriptomic dataset and integrated it with the Droplet Paired-Tag dataset to investigate how gene expression patterns and regulatory logic are spatially organized across the basal ganglia.

Data citation

No data citation listed

Funding agency

NIMH

Grant numbers

UM1MH130994

Access

open

License

CC BY 4.0