Integrated systems analysis reveals conserved gene networks underlying response to spinal cord injury

Abstract

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.

Data availability

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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Jordan W Squair

    International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Seth Tigchelaar

    International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Kyung-Mee Moon

    Centre for High-Throughput Biology, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Jie Liu

    International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Wolfram Tetzlaff

    International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3462-1676
  6. Brian K Kwon

    International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Andrei V Krassioukov

    International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Christopher R West

    International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Leonard J Foster

    Centre for High-Throughput Biology, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8551-4817
  10. Michael A Skinnider

    Centre for High-Throughput Biology, University of British Columbia, Vancouver, Canada
    For correspondence
    michaelskinnider@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2168-1621

Funding

Heart and Stroke Foundation of Canada

  • Christopher R West

Canadian Institutes of Health Research

  • Michael A Skinnider

Canadian Institutes of Health Research

  • Jordan W Squair

Genome Canada

  • Leonard J Foster

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

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.

Reviewing Editor

  1. Ole Kiehn, Karolinska Institutet, Sweden

Publication history

  1. Received: June 14, 2018
  2. Accepted: September 24, 2018
  3. Accepted Manuscript published: October 2, 2018 (version 1)
  4. Version of Record published: October 5, 2018 (version 2)

Copyright

© 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.

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  1. Jordan W Squair
  2. Seth Tigchelaar
  3. Kyung-Mee Moon
  4. Jie Liu
  5. Wolfram Tetzlaff
  6. Brian K Kwon
  7. Andrei V Krassioukov
  8. Christopher R West
  9. Leonard J Foster
  10. Michael A Skinnider
(2018)
Integrated systems analysis reveals conserved gene networks underlying response to spinal cord injury
eLife 7:e39188.
https://doi.org/10.7554/eLife.39188

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