Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Pittsburgh Center for Pain Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Cell Rep. 2024 Nov 26;43(11):114876. doi: 10.1016/j.celrep.2024.114876. Epub 2024 Oct 24.
Key mechanisms underlying chronic pain occur within the dorsal horn. Genome-wide association studies (GWASs) have identified genetic variants predisposed to chronic pain. However, most of these variants lie within regulatory non-coding regions that have not been linked to spinal cord biology. Here, we take a multi-species approach to determine whether chronic pain variants impact the regulatory genomics of dorsal horn neurons. First, we generate a large rhesus macaque single-nucleus RNA sequencing (snRNA-seq) atlas and integrate it with available human and mouse datasets to produce a single unified, species-conserved atlas of neuron subtypes. Cellular-resolution spatial transcriptomics in mouse shows the precise laminar location of these neuron subtypes, consistent with our analysis of neuron-subtype-selective markers in macaque. Using this cross-species framework, we generate a mouse single-nucleus open chromatin atlas of regulatory elements that shows strong and selective relationships between the neuron-subtype-specific chromatin regions and variants from major chronic pain GWASs.
慢性疼痛的主要机制发生在背角。全基因组关联研究（GWAS）已经确定了易患慢性疼痛的遗传变异。然而，这些变异大多数位于与脊髓生物学无关的调节性非编码区域。在这里，我们采用多物种方法来确定慢性疼痛变异是否会影响背角神经元的调节基因组。首先，我们生成了一个大型恒河猴单核 RNA 测序（snRNA-seq）图谱，并将其与现有的人类和小鼠数据集整合，生成了一个单一的、物种保守的神经元亚型图谱。在小鼠中的细胞分辨率空间转录组学显示了这些神经元亚型的精确层状位置，与我们在恒河猴中对神经元亚型选择性标记的分析一致。利用这种跨物种框架，我们生成了一个小鼠单核开放染色质调节元件图谱，显示了神经元亚型特异性染色质区域与主要慢性疼痛 GWAS 中变体之间的强烈和选择性关系。
