Conceptual modeling of mRNA decay provokes new hypotheses

PLoS One. 2014 Sep 25;9(9):e107085. doi: 10.1371/journal.pone.0107085. eCollection 2014.

Abstract

Biologists are required to integrate large amounts of data to construct a working model of the system under investigation. This model is often informal and stored mentally or textually, making it prone to contain undetected inconsistencies, inaccuracies, or even contradictions, not much less than a representation in free natural language. Using Object-Process Methodology (OPM), a formal yet visual and humanly accessible conceptual modeling language, we have created an executable working model of the mRNA decay process in Saccharomyces cerevisiae, as well as the import of its components to the nucleus following mRNA decay. We show how our model, which incorporates knowledge from 43 articles, can reproduce outcomes that match the experimental findings, evaluate hypotheses, and predict new possible outcomes. Moreover, we were able to analyze the effects of the mRNA decay model perturbations related to gene and interaction deletions, and predict the nuclear import of certain decay factors, which we then verified experimentally. In particular, we verified experimentally the hypothesis that Rpb4p, Lsm1p, and Pan2p remain bound to the RNA 3'-untranslated region during the entire process of the 5' to 3' degradation of the RNA open reading frame. The model has also highlighted erroneous hypotheses that indeed were not in line with the experimental outcomes. Beyond the scientific value of these specific findings, this work demonstrates the value of the conceptual model as an in silico vehicle for hypotheses generation and testing, which can reinforce, and often even replace, risky, costlier wet lab experiments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Cell Nucleus / metabolism
  • Models, Biological*
  • RNA Stability*
  • Reproducibility of Results
  • Saccharomyces cerevisiae / cytology
  • Saccharomyces cerevisiae / metabolism*

Grants and funding

This work was funded in part by the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement No. 262044 – VISIONAIR and from Gordon Center for Systems Engineering at the Technion (to DD). This work was funded, in part, by a grant from the Israel Science Foundation (to MC). GH is a recipient of the Gruss-Lipper family postdoctoral fellowship (EGL charitable foundation). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.