In a publication in Science this week, Schmiedel et al.  show that the reduction of cellular noise is a generic property of microRNA regulation that is linked to the repression of protein expression. As Hoffman & Pilpel (2015) put it: “MiRNAs serve as the cell’s noise cancelling headphones: when not subject to miRNAs regulation, mRNA levels can fluctuate randomly. However passing through the noise dampening machinery, the miRNAs, the mRNA’s expression level fluctuates less”.

The level of proteins in a cell can fluctuate over time even in a constant environment. These gene expression fluctuations, or noise, are generally believed to be harmful and are believed to impose fundamental limits on the precision of biological processes, such as the development of complex multicellular organisms and their maintenance.

Seminal work by the van Oudenaarden and others labs earlier pointed out that noise in the production of genes originates in the parts of the process with the fewest molecules involved, the mRNA level. A valid strategy for organisms to deal with noise is to use more mRNAs and translate them less efficiently to produce a certain amount of proteins. In the article published this week, Schmiedel et al. show that microRNAs, tiny pieces of RNA that bind to end of mRNAs, are potent noise reducers.

In the study, Schmiedel et al. use a combination of mathematical modelling and fluorescent reporter assays in mouse embryonic stem cells to show that microRNA regulation can reduce noise in the production of genes, which is most prevalent when genes are lowly expressed. On the other hand, microRNAs fluctuate themselves and these fluctuations can propagate to the regulated gene, adding to its fluctuations. This results in lowly expressed genes having reduced noise, but highly expressed genes having increased noise.

MicroRNAs are known to regulate genes in a combinatorial fashion, i.e. many different microRNAs simultaneously regulate a specific gene. Schmiedel et al. show that this property of microRNA regulation results in lowered propagation of microRNA fluctuations to the regulated gene and therefore optimizes overall noise reduction. These findings were translated to endogenous microRNA targets. With a combination of the reporter system and RNA sequencing, Schmiedel et al. suggest that microRNA regulation of endogenous targets results in robust noise reduction over the majority of expression levels of genes in mouse embryonic stem cells. Furthermore they show that hundreds of genes expressed within this range in mouse embryonic stem cells are strongly repressed by microRNAs, suggesting they should have reduced noise as a consequence of microRNA regulation in vivo.