Spinal cord injury (SCI) is a devastating neurological condition for which there are currently no effective treatment options to restore function. A major obstacle to the development of new therapies is our fragmentary understanding of the coordinated pathophysiological processes triggered by damage to the human spinal cord. Here, we describe a systems biology approach to integrate decades of small-scale experiments with unbiased, genome-wide gene expression from the human spinal cord, revealing a gene regulatory network signature of the pathophysiological response to SCI. Our integrative analyses converge on an evolutionarily conserved gene subnetwork enriched for genes associated with the response to SCI by small-scale experiments, and whose expression is upregulated in a severity-dependent manner following injury and downregulated in functional recovery. We validate the severity-dependent upregulation of this subnetwork in rodents in primary transcriptomic and proteomic studies. Our analysis provides a systems-level view of the coordinated molecular processes activated in response to SCI.
Sequencing data have been deposited in GEO under accession code GSE115067. They can be accessed at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE115067. Proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD010192. They can be accessed at https://www.ebi.ac.uk/pride/archive/projects/PXD010192.
- Christopher R West
- Michael A Skinnider
- Jordan W Squair
- Leonard J Foster
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Ethical approval was obtained by the University of British Columbia Behavioural Research Ethics Board (A14-0152) and all procedures strictly adhere to the guidelines issues by the Canadian Council for Animal Care.
- Ole Kiehn, Karolinska Institutet, Sweden
© 2018, Squair et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.