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MicroRNA control of protein expression noise

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Science  03 Apr 2015:
Vol. 348, Issue 6230, pp. 128-132
DOI: 10.1126/science.aaa1738

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Expressing variability under miRNA control

MicroRNAs (miRNAs) repress gene expression by inhibiting translation and increasing mRNA degradation. Schmiedel et al. used single-cell reporter experiments and mathematical modeling to show that miRNAs can reduce not just expression but the expression variability of target genes (see the Perspective by Hoffman and Pilpel). Combinatorial targeting principles ensured reduced variability for most miRNA gene targets. Thus, miRNAs may provide safeguards for the precision of gene expression during development or cellular homeostasis.

Science, this issue p. 128; see also p. 41

Abstract

MicroRNAs (miRNAs) repress the expression of many genes in metazoans by accelerating messenger RNA degradation and inhibiting translation, thereby reducing the level of protein. However, miRNAs only slightly reduce the mean expression of most targeted proteins, leading to speculation about their role in the variability, or noise, of protein expression. We used mathematical modeling and single-cell reporter assays to show that miRNAs, in conjunction with increased transcription, decrease protein expression noise for lowly expressed genes but increase noise for highly expressed genes. Genes that are regulated by multiple miRNAs show more-pronounced noise reduction. We estimate that hundreds of (lowly expressed) genes in mouse embryonic stem cells have reduced noise due to substantial miRNA regulation. Our findings suggest that miRNAs confer precision to protein expression and thus offer plausible explanations for the commonly observed combinatorial targeting of endogenous genes by multiple miRNAs, as well as the preferential targeting of lowly expressed genes.

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