title: Timescales and bottlenecks in miRNA-dependent gene regulation.
abstract: MiRNAs are post-transcriptional regulators that contribute to the establishment and maintenance of gene expression patterns. Although their biogenesis and decay appear to be under complex control, the implications of miRNA expression dynamics for the processes that they regulate are not well understood. We derived a mathematical model of miRNA-mediated gene regulation, inferred its parameters from experimental data sets, and found that the model describes well time-dependent changes in mRNA, protein and ribosome density levels measured upon miRNA transfection and induction. The inferred parameters indicate that the timescale of miRNA-dependent regulation is slower than initially thought. Delays in miRNA loading into Argonaute proteins and the slow decay of proteins relative to mRNAs can explain the typically small changes in protein levels observed upon miRNA transfection. For miRNAs to regulate protein expression on the timescale of a day, as miRNAs involved in cell-cycle regulation do, accelerated miRNA turnover is necessary.
authors.affiliation: Biozentrum, University of Basel and Swiss Institute of Bioinformatics, Basel, Switzerland.
authors.forename: Jean
authors.initials: J
authors.lastname: Hausser
authors.forename: Afzal Pasha
authors.initials: AP
authors.lastname: Syed
authors.forename: Nathalie
authors.initials: N
authors.lastname: Selevsek
authors.forename: Erik
authors.initials: E
authors.lastname: van Nimwegen
authors.forename: Lukasz
authors.initials: L
authors.lastname: Jaskiewicz
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.forename: Mihaela
authors.initials: M
authors.lastname: Zavolan
mesh_terms: D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology; D008957:Models, Genetic; D015203:Reproducibility of Results
chemical_list: D060565:Argonaute Proteins; D035683:MicroRNAs