Co-Expression Network Approach to Studying the Effects of Botulinum Neurotoxin-A

Kavitha Mukund, Samuel R. Ward, Richard L. Lieber, Shankar Subramaniam

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Botulinum Neurotoxin A (BoNT-A) is a potent neurotoxin with several clinical applications. The goal of this study was to utilize co-expression network theory to analyze temporal transcriptional data from skeletal muscle after BoNT-A treatment. Expression data for 2000 genes (extracted using a ranking heuristic) served as the basis for this analysis. Using weighted gene co-expression network analysis (WGCNA), we identified 19 co-expressed modules, further hierarchically clustered into five groups. Quantifying average expression and co-expression patterns across these groups revealed temporal aspects of muscle's response to BoNT-A. Functional analysis revealed enrichment of group 1 with metabolism; group 5 with contradictory functions of atrophy and cellular recovery; and groups 2 and 3 with extracellular matrix (ECM) and non-fast fiber isoforms. Topological positioning of two highly ranked, significantly expressed genes - Dclk1 and Ostalpha - within group 5 suggested possible mechanistic roles in recovery from BoNT-A induced atrophy. Phenotypic correlations of groups with titin and myosin protein content further emphasized the effect of BoNT-A on the sarcomeric contraction machinery in early phase of chemodenervation. In summary, our approach revealed a hierarchical functional response to BoNT-A induced paralysis with early metabolic and later ECM responses and identified putative biomarkers associated with chemodenervation. Additionally, our results provide an unbiased validation of the response documented in our previous work.

Original languageEnglish (US)
Article number8070322
Pages (from-to)2009-2016
Number of pages8
JournalIEEE/ACM Transactions on Computational Biology and Bioinformatics
Volume15
Issue number6
DOIs
StatePublished - Nov 1 2018

Keywords

  • Co-expression networks
  • botox
  • clustering
  • cross sectional temporal data
  • gene ranking
  • muscle
  • timecourse

ASJC Scopus subject areas

  • Biotechnology
  • Genetics
  • Applied Mathematics

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