Endogenous transcripts control miRNA levels and activity in mammalian cells by target-directed miRNA degradation

Francesco Ghini, Carmela Rubolino, Montserrat Climent, Ines Simeone, Matteo J. Marzi () and Francesco Nicassio ()
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Francesco Ghini: Istituto Italiano di Tecnologia (IIT)—Via Adamello 16
Carmela Rubolino: Istituto Italiano di Tecnologia (IIT)—Via Adamello 16
Montserrat Climent: Istituto Italiano di Tecnologia (IIT)—Via Adamello 16
Ines Simeone: Istituto Italiano di Tecnologia (IIT)—Via Adamello 16
Matteo J. Marzi: Istituto Italiano di Tecnologia (IIT)—Via Adamello 16
Francesco Nicassio: Istituto Italiano di Tecnologia (IIT)—Via Adamello 16

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Little is known about miRNA decay. A target-directed miRNA degradation mechanism (TDMD) has been suggested, but further investigation on endogenous targets is necessary. Here, we identify hundreds of targets eligible for TDMD and show that an endogenous RNA (Serpine1) controls the degradation of two miRNAs (miR-30b-5p and miR-30c-5p) in mouse fibroblasts. In our study, TDMD occurs when the target is expressed at relatively low levels, similar in range to those of its miRNAs (100–200 copies per cell), and becomes more effective at high target:miRNA ratios (>10:1). We employ CRISPR/Cas9 to delete the miR-30 responsive element within Serpine1 3'UTR and interfere with TDMD. TDMD suppression increases miR-30b/c levels and boosts their activity towards other targets, modulating gene expression and cellular phenotypes (i.e., cell cycle re-entry and apoptosis). In conclusion, a sophisticated regulatory layer of miRNA and gene expression mediated by specific endogenous targets exists in mammalian cells.

Date: 2018
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DOI: 10.1038/s41467-018-05182-9

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