A Multimodal Single-Cell Epigenomic and 3D Genome Atlas of the Human Basal Ganglia
- Publicada
- Servidor
- bioRxiv
- DOI
- 10.64898/2026.02.12.705594
The basal ganglia (BG) underlie motor control, reward processing, and many neurological and psychiatric disorders, but a comprehensive epigenomic and 3D-genome atlas of the human BG is lacking. Here we present a multimodal single-cell atlas profiling DNA methylation and 3D chromatin conformation in 261,331 nuclei (snm3C-seq) across eight subregions, resolving 12 classes, 31 subclasses, and 59 groups. Harmonized under the HMBA basal-ganglia consensus taxonomy, this atlas integrates with matched RNA, ATAC-seq, and histone-modification data across five regulatory layers. We identify millions of cell-type- and region-specific differentially methylated regions enriched for distinct transcription factor motifs and link them to disease-associated heritability. Neuron-specific loops dominate cell-type-specific 3D contact remodeling, while most non-neuron-specific loops are constitutive. Among spiny projection neurons (SPNs), chromatin loops, rather than TAD boundaries, distinguish D1, D2, and eccentric SPN subclasses, with eccentric SPNs showing the most loop-level reorganization among the three. We characterize STR D2 SMYD2-HTR7 SPN, a newly recognized POU6F2⁺ D2-SPN subtype, and reveal region-specific methylation and contact gradients of disease-associated genes, including CADM1 and PDE8B. Integrative gene-regulatory networks reconstruct cell-type-resolved enhancer-promoter links to interpret Parkinson’s disease risk variants at SNCA. Finally, MERFISH spatial profiling combined with cross-species Patch-seq identifies non-SPN neuronal subtypes, including a MOXD1⁺ striosomal STR FS PTHLH-PVALB GABA subtype with distinct electrophysiology, partitioning across the striatal matrix-striosome boundary.
Highlights
A multimodal single-cell atlas maps DNA methylation and 3D genome architecture across human basal ganglia cell types and subregions.
Neuron-specific loops dominate cell-type-specific 3D contact remodeling in the human BG, whereas most non-neuron-specific loops are constitutive.
Spiny Projection Neuron (SPN) subtypes exhibit regionally organized epigenomic and 3D genome signatures that align with dorsal-ventral identities.
Chromatin loops are the primary distinguishing feature among D1, D2, and eccentric SPN subclasses, with eccentric SPNs being the most 3D-reorganized.
Integrated regulatory maps link cell-type-specific enhancers to disease-associated genetic risk in the human basal ganglia.
Non-SPN interneurons differ in distribution and in transcriptional and epigenetic identity across the matrix-striosome boundary.