Cell Reports (Nov 2024)
Spatial, transcriptomic, and epigenomic analyses link dorsal horn neurons to chronic pain genetic predisposition
- Cynthia M. Arokiaraj,
- Michael J. Leone,
- Michael Kleyman,
- Alexander Chamessian,
- Myung-Chul Noh,
- BaDoi N. Phan,
- Bettega C. Lopes,
- Kelly A. Corrigan,
- Vijay Kiran Cherupally,
- Deepika Yeramosu,
- Michael E. Franusich,
- Riya Podder,
- Sumitra Lele,
- Stephanie Shiers,
- Byungsoo Kang,
- Meaghan M. Kennedy,
- Viola Chen,
- Ziheng Chen,
- Hansruedi Mathys,
- Richard P. Dum,
- David A. Lewis,
- Yawar Qadri,
- Theodore J. Price,
- Andreas R. Pfenning,
- Rebecca P. Seal
Affiliations
- Cynthia M. Arokiaraj
- 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
- Michael J. Leone
- 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
- Michael Kleyman
- Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Alexander Chamessian
- Department of Anesthesiology, Duke University Medical Center, Durham, NC 27708, USA; Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, USA
- Myung-Chul Noh
- 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
- BaDoi N. Phan
- 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
- Bettega C. Lopes
- 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
- Kelly A. Corrigan
- 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
- Vijay Kiran Cherupally
- Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Deepika Yeramosu
- Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Michael E. Franusich
- Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Riya Podder
- Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Sumitra Lele
- Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Stephanie Shiers
- Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, USA
- Byungsoo Kang
- Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Meaghan M. Kennedy
- Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Viola Chen
- Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Ziheng Chen
- Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Department of Biological Sciences, Mellon College of Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Hansruedi Mathys
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Richard P. Dum
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- David A. Lewis
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Yawar Qadri
- Department of Anesthesiology, Emory University, Atlanta, GA 30038, USA
- Theodore J. Price
- Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, USA
- Andreas R. Pfenning
- Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Corresponding author
- Rebecca P. Seal
- 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 Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Corresponding author
- Journal volume & issue
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Vol. 43,
no. 11
p. 114876
Abstract
Summary: 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.
