Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder. However, cell type–dependent transcriptional regulatory programs responsible for PD pathogenesis remain elusive. Here, we establish transcriptomic and epigenomic landscapes of the substantia nigra by profiling 113,207 nuclei obtained from healthy controls and patients with PD. Our multiomics data integration provides cell type annotation of 128,724 cis-regulatory elements (cREs) and uncovers cell type–specific dysregulations in cREs with a strong transcriptional influence on genes implicated in PD. The establishment of high-resolution three-dimensional chromatin contact maps identifies 656 target genes of dysregulated cREs and genetic risk loci, uncovering both potential and known PD risk genes. Notably, these candidate genes exhibit modular gene expression patterns with unique molecular signatures in distinct cell types, highlighting altered molecular mechanisms in dopaminergic neurons and glial cells including oligodendrocytes and microglia. Together, our single-cell transcriptome and epigenome reveal cell type–specific disruption in transcriptional regulations related to PD.

Results

Figure1

Figure1 shows single-nucleus profiling of transcriptomic and epigenomic landscape in the human SN.

Figure2

Figure2 shows dysregulation of cREs shaping PD-specific gene expression.

Figure3

Figure3 shows target gene inference for noncoding regulatory sequences through 3D chromatin contacts

Figure4

Figure4 shows the characterization of PD “WAS-SNPs based on celltype–resolved epigenomic landscape.

Figure5

Figure5 shows altered motif binding affinity for active TFs in the PD GWAS-SNP–containing cREs.

Figure6

Figure6 shows analysis of modular gene expression patterns across putative PD genes.

Reference