Mirnas

Downloaded from rnajournal.cshlp.org on February 19, 2013 - Published by Cold Spring Harbor Laboratory Press

Kinetic signatures of microRNA modes of action
Nadya Morozova, Andrei Zinovyev, Nora Nonne, et al. RNA 2012 18: 1635-1655 originally published online July 31, 2012 Access the most recent version at doi:10.1261/rna.032284.112

Supplemental Material Referenceshttp://rnajournal.cshlp.org/content/suppl/2012/07/11/rna.032284.112.DC1.html This article cites 91 articles, 37 of which can be accessed free at: http://rnajournal.cshlp.org/content/18/9/1635.full.html#ref-list-1 Article cited in: http://rnajournal.cshlp.org/content/18/9/1635.full.html#related-urls

Email alerting service

Receive free email alerts when new articles cite this article - sign up in the box at the topright corner of the article or click here

To subscribe to RNA go to: http://rnajournal.cshlp.org/subscriptions

Copyright © 2012 RNA Society

Downloaded from rnajournal.cshlp.org on February 19, 2013 - Published by Cold Spring Harbor Laboratory Press

Kinetic signatures of microRNA modes of action
NADYA MOROZOVA,1,2,7 ANDREI ZINOVYEV,3,4,5,7 NORA NONNE,1,2 LINDA-LOUISE PRITCHARD,1,2ALEXANDER N. GORBAN,6 and ANNICK HAREL-BELLAN1,2,8
1 3

´ CNRS FRE 3377, CEA Saclay, and 2Universite Paris-Sud, F-91191, Gif-sur-Yvette, France Institut Curie, Service Bioinformatique, F-75248 Paris, France 4 Ecole des Mines ParisTech, F-77300 Fontainebleau, France 5 INSERM, U900, Paris, F-75248, France 6 University of Leicester, Centre for Mathematical Modelling, Leicester, LE1 7RH, UnitedKingdom

ABSTRACT MicroRNAs (miRNAs) are key regulators of all important biological processes, including development, differentiation, and cancer. Although remarkable progress has been made in deciphering the mechanisms used by miRNAs to regulate translation, many contradictory findings have been published that stimulate active debate in this field. Here we contribute to this discussion in threeways. First, based on a comprehensive analysis of the existing literature, we hypothesize a model in which all proposed mechanisms of microRNA action coexist, and where the apparent mechanism that is detected in a given experiment is determined by the relative values of the intrinsic characteristics of the target mRNAs and associated biological processes. Among several coexisting miRNA mechanisms, theone that will effectively be measurable is that which acts on or changes the sensitive parameters of the translation process. Second, we have created a mathematical model that combines nine known mechanisms of miRNA action and estimated the model parameters from the literature. Third, based on the mathematical modeling, we have developed a computational tool for discriminating among differentpossible individual mechanisms of miRNA action based on translation kinetics data that can be experimentally measured (kinetic signatures). To confirm the discriminatory power of these kinetic signatures and to test our hypothesis, we have performed several computational experiments with the model in which we simulated the coexistence of several miRNA action mechanisms in the context of variableparameter values of the translation. Keywords: microRNA; kinetic rates; mathematical modeling; dominant systems

INTRODUCTION MicroRNA (miRNAs) are short (21–23-nt-long) noncoding RNAs that negatively regulate gene expression. MiRNAs are currently considered to be modulators of a wide variety of biological pathways, including development, differentiation, and oncogenesis. Mature miRNAs are processedfrom long transcripts and are incorporated into the RISC complex, whose key component is an Argonaute protein. MiRNAs regulate gene expression by guiding the RISC complex toward specific target mRNAs. The exact mode of action of the RISC complex is still a matter of debate. Several distinct mechanisms have been reported in many studies (Esquela-Kerscher and Slack 2006; Kloosterman and Plasterk...