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MicroRNA function can be reversed by altering target gene expression levels

ABSTRACT: Summary Paradoxically, many microRNAs appear to exhibit entirely opposite functions when placed in different contexts. For example, miR-125b has been shown to be pro-apoptotic in some studies, but anti-apoptotic in others. To investigate this phenomenon, we combine computational modeling with experimental approaches to examine how the function of miR-125b in apoptosis varies with respect to the expression levels of its pro-apoptotic and anti-apoptotic targets. In doing so, we elucidate a general trend that miR-125b is more pro-apoptotic when its anti-apoptotic targets are overexpressed, whereas it is more anti-apoptotic when its pro-apoptotic targets are overexpressed. We show that it is possible to completely reverse miR-125b′s function in apoptosis by modifying the expression levels of its target genes. Furthermore, miR-125b′s function may also be altered by the presence of anticancer drugs. These results suggest that the function of a microRNA can vary substantially and is dependent on its target gene expression levels. Graphical abstract Highlights • Many miRNAs exhibit entirely opposite functions when placed in different contexts• miR-125b can be pro- or anti-apoptotic depending on target gene expression levels• The function of a miRNA can be reversed by altering target gene expression levels• The presence of anticancer drugs can also alter a miRNA's function Molecular biology; Molecular mechanism of gene regulation; Cell biology; Computational bioinformatics.

SUBMITTER: Svoronos A

PROVIDER: S-EPMC8560630 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The family of microRNAs (miRNAs) not only plays an important role in gene regulation but is also useful for the diagnosis of diseases. A reliable method with high sensitivity may allow researchers to detect slight fluctuations in ultra-trace amounts of miRNA. In this study, we propose a sensitive imaging method for the direct probing of miR-10b (miR-10b-3p, also called miR-10b*) and its target (HOXD10 mRNA) in fixed cells based on the specific recognition of molecular beacons combined with highly inclined and laminated optical sheet (HILO) fluorescence microscopy. The designed dye-quencher-labelled molecular beacons offer excellent efficiencies of fluorescence resonance energy transfer that allow us to detect miRNA and the target mRNA simultaneously in hepatocellular carcinoma cells using HILO fluorescence microscopy. Not only can the basal trace amount of miRNA be observed in each individual cell, but the obtained images also indicate that this method is useful for monitoring the fluctuations in ultra-trace amounts of miRNA when the cells are transfected with a miRNA precursor or a miRNA inhibitor (anti-miR). Furthermore, a reasonable causal relation between the miR-10b and HOXD10 expression levels was observed in miR-10b* precursor-transfected cells and miR-10b* inhibitor-transfected cells. The trends of the miRNA alterations obtained using HILO microscopy completely matched the RT-qPCR data and showed remarkable reproducibility (the coefficient of variation [CV] = 0.86%) and sensitivity (<1.0 fM). This proposed imaging method appears to be useful for the simultaneous visualisation of ultra-trace amounts of miRNA and target mRNA and excludes the procedures for RNA extraction and amplification. Therefore, the visualisation of miRNA and the target mRNA should facilitate the exploration of the functions of ultra-trace amounts of miRNA in fixed cells in biological studies and may serve as a powerful tool for diagnoses based on circulating cancer cells.

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MicroRNA function can be reversed by altering target gene expression levels

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