Timescales and bottlenecks in miRNA-dependent gene regulation

Abstract

• A mathematical model links the dynamics of miRNA expression and loading into the Argonaute protein to the dynamics of miRNA targets.

• Loading of miRNAs into Argonaute and the slow decay of proteins impose two bottlenecks on the speed of miRNA-mediated regulation.

• Accelerated miRNA turnover is necessary for regulating target expression on the timescale of a day.

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.