MiRNAs confer phenotypic robustness to gene networks by suppressing biological noise

Nat Commun. 2013;4:2364. doi: 10.1038/ncomms3364.

Abstract

miRNAs are small non-coding RNAs able to modulate target gene expression. It has been postulated that miRNAs confer robustness to biological processes, but clear experimental evidence is still missing. Here, using a synthetic biological approach, we demonstrate that microRNAs provide phenotypic robustness to transcriptional regulatory networks by buffering fluctuations in protein levels. We construct a network motif in mammalian cells exhibiting a 'toggle-switch' phenotype in which two alternative protein expression levels define its ON and OFF states. The motif consists of an inducible transcription factor that self-regulates its own transcription and that of a miRNA against the transcription factor itself. We confirm, using mathematical modelling and experimental approaches, that the microRNA confers robustness to the toggle-switch by enabling the cell to maintain and transmit its state. When absent, a dramatic increase in protein noise level occurs, causing the cell to randomly switch between the two states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cricetulus
  • E2F1 Transcription Factor / genetics*
  • E2F1 Transcription Factor / metabolism
  • Feedback, Physiological*
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Genetic Vectors
  • Lentivirus / genetics
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Models, Genetic*
  • Phenotype*
  • Protein Biosynthesis
  • Stochastic Processes
  • Synthetic Biology
  • Transcription, Genetic

Substances

  • E2F1 Transcription Factor
  • MicroRNAs