A network-based method to assess the statistical significance of mild co-regulation effects

PLoS One. 2013 Sep 9;8(9):e73413. doi: 10.1371/journal.pone.0073413. eCollection 2013.

Abstract

Recent development of high-throughput, multiplexing technology has initiated projects that systematically investigate interactions between two types of components in biological networks, for instance transcription factors and promoter sequences, or microRNAs (miRNAs) and mRNAs. In terms of network biology, such screening approaches primarily attempt to elucidate relations between biological components of two distinct types, which can be represented as edges between nodes in a bipartite graph. However, it is often desirable not only to determine regulatory relationships between nodes of different types, but also to understand the connection patterns of nodes of the same type. Especially interesting is the co-occurrence of two nodes of the same type, i.e., the number of their common neighbours, which current high-throughput screening analysis fails to address. The co-occurrence gives the number of circumstances under which both of the biological components are influenced in the same way. Here we present SICORE, a novel network-based method to detect pairs of nodes with a statistically significant co-occurrence. We first show the stability of the proposed method on artificial data sets: when randomly adding and deleting observations we obtain reliable results even with noise exceeding the expected level in large-scale experiments. Subsequently, we illustrate the viability of the method based on the analysis of a proteomic screening data set to reveal regulatory patterns of human microRNAs targeting proteins in the EGFR-driven cell cycle signalling system. Since statistically significant co-occurrence may indicate functional synergy and the mechanisms underlying canalization, and thus hold promise in drug target identification and therapeutic development, we provide a platform-independent implementation of SICORE with a graphical user interface as a novel tool in the arsenal of high-throughput screening analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Cell Line, Tumor
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Humans
  • MicroRNAs / genetics*
  • Proteomics / methods*
  • Signal Transduction*

Substances

  • MicroRNAs
  • ErbB Receptors

Grants and funding

EAH is supported by the Heidelberg Graduate School of Mathematical and Computational Methods for the Sciences, University of Heidelberg, Germany, which is funded by the German Excellence Initiative (GSC 220): http://www.mathcomp.uni-heidelberg.de/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.