miRNAs as Global Regulators: How Global Are We Talking Here?

Source: Selbach et al (2008). Widespread changes in protein synthesis induced by microRNAs. Nature 455:58-63.

miRNAs comprise a major set of post-transcriptional regulators with profound effects on different cellular processes through gene expression regulation. This paper is the first of its kind to monitor the large-sclae effects of deregulations in miRNA expression. Despite their apparent importance, we know little about the depth of regulation by miRNAs. Are there any miRNA master-regulators? How many gene on average are regulated by these small RNAs?

In this paper, the authors use state-of-the-art technologies to detect and compare protein levels in the absence, presence or over-expression of certain miRNAs. In their setup, they start with miRNA transfection into HeLa cells. 8hr post-infection, they label the transfected cells with heavy isotopes of amino acids while using medium-heavy for control samples. They combine the samples and through comparing the heavy to medium-heavy ratio from the mass-spectra, they comment on the abundance of the proteins.

They first show that the mRNAs downregulated in the presence of excessive miRNAs are enriched in the target seed. They subsequently make predictions about which mRNAs are directly targeted by each miRNA.

The take home message from this paper is the fact that the miRNAs affect a large spectrum of proteins... much higher than what we imagined before. For example, the authors show that let-7 regulates the expression of thousands of proteins in the cell.