Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Sci Adv. 2023 Apr 14;9(15):eabo2467. doi: 10.1126/sciadv.abo2467.
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.
帕金森病（PD）是一种进行性神经退行性疾病。然而，导致 PD 发病的细胞类型依赖性转录调控程序仍难以捉摸。在这里，我们通过对来自健康对照者和 PD 患者的 113207 个核进行分析，建立了黑质的转录组和表观基因组图谱。我们的多组学数据整合提供了 128724 个顺式调控元件（cRE）的细胞类型注释，并揭示了 cRE 的细胞类型特异性失调，这些 cRE 对涉及 PD 的基因具有强烈的转录影响。高分辨率三维染色质接触图谱的建立确定了 656 个失调 cRE 和遗传风险位点的靶基因，揭示了潜在的和已知的 PD 风险基因。值得注意的是，这些候选基因表现出具有独特分子特征的模块化基因表达模式，突出了多巴胺能神经元和神经胶质细胞（包括少突胶质细胞和小胶质细胞）中改变的分子机制。总之，我们的单细胞转录组和表观基因组揭示了与 PD 相关的转录调控的细胞类型特异性破坏。
