MicroRNAs can generate thresholds in target gene expression

By S. Mukherji, Margaret S. Ebert, Grace X. Y. Zheng, John S. Tsang, Phillip A. Sharp, Alexander van Oudenaarden. Nature Genetics, 2011

674 citations recorded by the source corpus.

MicroRNAs (miRNAs) are short, highly conserved noncoding RNA molecules that repress gene expression in a sequence-dependent manner. We performed single-cell measurements using quantitative fluorescence microscopy and flow cytometry to monitor a target gene's protein expression in the presence and absence of regulation by miRNA. We find that although the average level of repression is modest, in agreement with previous population-based measurements, the repression among individual cells varies dramatically. In particular, we show that regulation by miRNAs establishes a threshold level of target mRNA below which protein production is highly repressed. Near this threshold, protein expression responds sensitively to target mRNA input, consistent with a mathematical model of molecular titration. These results show that miRNAs can act both as a switch and as a fine-tuner of gene expression.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6feda9f9ab85bc07e871189d5f50d37a2e4a46d1

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Citations in the corpus

Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. (2014, background): “Highly expressed, site-containing RNAs, either found naturally or delivered as research reagents, can act as “sponges” to titrate miRNAs away from other normal targets (Ebert et al., 2007; Franco-Zorrilla et al., 2007; Mukherji et al., 2011; Hansen et al., 2013; Memczak et al., 2013).”
Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp™ (2014, background): “Highly expressed site-containing RNAs, either found naturally or delivered as research reagents, can act as ‘‘sponges’’ to titrate miRNAs away from other normal targets (Ebert et al., 2007; Franco-Zorrilla et al., 2007; Mukherji et al., 2011; Hansen et al., 2013; Memczak et al., 2013).”
The Imprinted H19 LncRNA Antagonizes Let-7 MicroRNAs (2013, background): “…of let-7 targets Dicer and Hmga2 decreased in response to increased let-7 function, a phenomenon that was not observed in proliferating HEK293 (Figure 4) or HUVEC (Supplemental Figure S1C, D) cells, consistent with context-dependent miRNA effects (Ebert and Sharp, 2012; Mukherji et al., 2011).”
Roles for microRNAs in conferring robustness to biological processes. (2012, positive): “Recently, it was shown that miRNA target genes have an mRNA expression threshold below which the gene is efficiently repressed and above which it can overwhelm the available miRNA (Mukherji et al., 2011).”