Dynamics of regulatory networks in gastrin-treated adenocarcinoma cells

PLoS One. 2014 Jan 8;9(1):e78349. doi: 10.1371/journal.pone.0078349. eCollection 2014.

Abstract

Understanding gene transcription regulatory networks is critical to deciphering the molecular mechanisms of different cellular states. Most studies focus on static transcriptional networks. In the current study, we used the gastrin-regulated system as a model to understand the dynamics of transcriptional networks composed of transcription factors (TFs) and target genes (TGs). The hormone gastrin activates and stimulates signaling pathways leading to various cellular states through transcriptional programs. Dysregulation of gastrin can result in cancerous tumors, for example. However, the regulatory networks involving gastrin are highly complex, and the roles of most of the components of these networks are unknown. We used time series microarray data of AR42J adenocarcinoma cells treated with gastrin combined with static TF-TG relationships integrated from different sources, and we reconstructed the dynamic activities of TFs using network component analysis (NCA). Based on the peak expression of TGs and activity of TFs, we created active sub-networks at four time ranges after gastrin treatment, namely immediate-early (IE), mid-early (ME), mid-late (ML) and very late (VL). Network analysis revealed that the active sub-networks were topologically different at the early and late time ranges. Gene ontology analysis unveiled that each active sub-network was highly enriched in a particular biological process. Interestingly, network motif patterns were also distinct between the sub-networks. This analysis can be applied to other time series microarray datasets, focusing on smaller sub-networks that are activated in a cascade, allowing better overview of the mechanisms involved at each time range.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Cell Line, Tumor
  • Gastrins / pharmacology*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Regulatory Networks / drug effects*
  • Humans
  • Molecular Sequence Annotation
  • Nucleotide Motifs / genetics
  • Transcription Factors / metabolism

Substances

  • Gastrins
  • Transcription Factors

Grants and funding

This work was funded by Research Council of Norway (project number : 70174300). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.