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The miRNA–target interactions: An underestimated intricacy

Diener, Caroline, Keller, Andreas, Meese, Eckart·2024·Nucleic Acids Research
DOI 10.1093/nar/gkad1142PMC PMC10899768
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Abstract

MicroRNAs (miRNAs) play indispensable roles in posttranscriptional gene regulation. Their cellular regulatory impact is determined not solely by their sheer number, which likely amounts to >2000 individual miRNAs in human, than by the regulatory effectiveness of single miRNAs. Although, one begins to develop an understanding of the complex mechanisms underlying miRNA–target interactions (MTIs), the overall knowledge of MTI functionality is still rather patchy. In this critical review, we summarize key features of mammalian MTIs. We especially highlight latest insights on (i) the dynamic make-up of miRNA binding sites including non-canonical binding sites, (ii) the cooperativity between miRNA binding sites, (iii) the adaptivity of MTIs through sequence modifications, (iv) the bearing of intra-cellular miRNA localization changes and (v) the role of cell type and cell status specific miRNA interaction partners. The MTI biology is discussed against the background of state-of-the-art approaches with particular emphasis on experimental strategies for evaluating miRNA functionality.

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Graphical Abstract CC BY · PubMed Central
Figure 1. Scheme of the canonical miRNA biogenesis pathway. The first step of the canonical mammalian miRNA biogenesis encompasses the transcription of a primary miRNA (pri-miRNA) from endogenous DNA loci by RNA polymerase II. The primary transcript includes an imperfect hairpin structure that is cleaved by the DROSHA-DGCR8 complex into a 60–90 nt long precursor miRNA (pre-miRNA) with a two nucleotide (nt) 3′ overhang. The pre-miRNA is transported from the nucleus to cytoplasm through the export protein XPO5 in a RAN-GTP dependent manner. The cytoplasmatic miRNA becomes a substrate for the RNase DICER that forms a complex with the double-stranded RNA-binding protein TRBP. Following removal of the loop structure, a miRNA duplex of 19–22 nt in length interacts with proteins of the Argonaute (Ago) family. One strand is incorporated into the RNA induced silencing complex (RISC). The strand with a higher content of purines and a lower thermodynamic stability of the 5′ end takes the dominant biological functionality i.e. it acts as functional miRNA that confers post-transcriptional regulation through RISC catalyzed mRNA degradation, mRNA destabilization or translation repression. [The functional portion of the miRNAs are indicated in red, the mRNA target is shown as a solid blue line, and the degraded mRNA as a dashed blue line. Interactions between miRNA and mRNA are indicated by opposite comb-shaped lines. The Drosha–DGCR8 complex is depicted by pink bodies, the export protein XPO5 by a violet cylinder, the DICER-TRBP complex by blue bodies, the RISC by a turquoise body and ribosomes by green bodies.]
Figure 1. Scheme of the canonical miRNA biogenesis pathway. The first step of the canonical mammalian miRNA biogenesis encompasses the transcription of a primary miRNA (pri-miRNA) from endogenous DNA loci by RNA polymerase II. The primary transcript includes an imperfect hairpin structure that is cleaved by the DROSHA-DGCR8 complex into a 60–90 nt long precursor miRNA (pre-miRNA) with a two nucleotide (nt) 3′ overhang. The pre-miRNA is transported from the nucleus to cytoplasm through the export protein XPO5 in a RAN-GTP dependent manner. The cytoplasmatic miRNA becomes a substrate for the RNase DICER that forms a complex with the double-stranded RNA-binding protein TRBP. Following removal of the loop structure, a miRNA duplex of 19–22 nt in length interacts with proteins of the Argonaute (Ago) family. One strand is incorporated into the RNA induced silencing complex (RISC). The strand with a higher content of purines and a lower thermodynamic stability of the 5′ end takes the dominant biological functionality i.e. it acts as functional miRNA that confers post-transcriptional regulation through RISC catalyzed mRNA degradation, mRNA destabilization or translation repression. [The functional portion of the miRNAs are indicated in red, the mRNA target is shown as a solid blue line, and the degraded mRNA as a dashed blue line. Interactions between miRNA and mRNA are indicated by opposite comb-shaped lines. The Drosha–DGCR8 complex is depicted by pink bodies, the export protein XPO5 by a violet cylinder, the DICER-TRBP complex by blue bodies, the RISC by a turquoise body and ribosomes by green bodies.]CC BY · PubMed Central
Figure 2. Overview on miRNA–target bindings and miRNA localization changes. (A) The regulatory capacity of MTIs is a function of the length of binding interaction between the miRNA seed sequence and the mRNA target, the presence of 3′ binding sites, the cooperation between multiple miRNA-responsive elements and the modification of both, the miRNAs and target sequences through e.g. A-to-I RNA editing or 3′UTR shortening. (B) Intra-cellular miRNA sub-localizations include membranous comparts like the nucleus or mitochondria and non-membranous comparts like granules. Extracellular miRNA localization can result from secretion of vesicles like exosomes. [MiRNAs are indicated as red lines, mRNAs as blue lines, interactions between miRNA and mRNA by opposite comb-shaped lines. Length variations are depicted by dashed two-sided arrows and translocations by solid two-sides arrows. Ribosomes are shown as green bodies, RISC as turquoise bodies. Sequence shortening is symbolized by cutting scissors and sequence exchanges by dotted rectangles.]
Figure 2. Overview on miRNA–target bindings and miRNA localization changes. (A) The regulatory capacity of MTIs is a function of the length of binding interaction between the miRNA seed sequence and the mRNA target, the presence of 3′ binding sites, the cooperation between multiple miRNA-responsive elements and the modification of both, the miRNAs and target sequences through e.g. A-to-I RNA editing or 3′UTR shortening. (B) Intra-cellular miRNA sub-localizations include membranous comparts like the nucleus or mitochondria and non-membranous comparts like granules. Extracellular miRNA localization can result from secretion of vesicles like exosomes. [MiRNAs are indicated as red lines, mRNAs as blue lines, interactions between miRNA and mRNA by opposite comb-shaped lines. Length variations are depicted by dashed two-sided arrows and translocations by solid two-sides arrows. Ribosomes are shown as green bodies, RISC as turquoise bodies. Sequence shortening is symbolized by cutting scissors and sequence exchanges by dotted rectangles.]CC BY · PubMed Central
Figure 3. Scheme representation on the diversity of miRNA interactomes. (A) Different miRNAs compete for cellular resources, including the available RISCs. There are specific preferences of the miRNAs for their interaction with different Ago paralogs as central part of the RISC. (B) Target mRNAs and competing endogenous RNA species, like circular RNAs (circRNAs), contest for miRNA binding. (C) Different mRNAs compete for RISC bound miRNAs. (D) RNA-binding proteins (RBPs) modulate accessibility of a mRNA target site for miRNAs. [Different miRNAs are depicted in red, pink and orange, respectively. Different mRNAs (targets) are shown in shades of blue and ceRNAs in violet. A different molecular abundance is indicated by a different number of miRNAs or mRNAs, respectively. RISCs are shown by turquoise and RNA binding proteins by greyish bodies. Functional interactions are indicated by arrows and sequence interactions by opposite comb-shaped lines.]
Figure 3. Scheme representation on the diversity of miRNA interactomes. (A) Different miRNAs compete for cellular resources, including the available RISCs. There are specific preferences of the miRNAs for their interaction with different Ago paralogs as central part of the RISC. (B) Target mRNAs and competing endogenous RNA species, like circular RNAs (circRNAs), contest for miRNA binding. (C) Different mRNAs compete for RISC bound miRNAs. (D) RNA-binding proteins (RBPs) modulate accessibility of a mRNA target site for miRNAs. [Different miRNAs are depicted in red, pink and orange, respectively. Different mRNAs (targets) are shown in shades of blue and ceRNAs in violet. A different molecular abundance is indicated by a different number of miRNAs or mRNAs, respectively. RISCs are shown by turquoise and RNA binding proteins by greyish bodies. Functional interactions are indicated by arrows and sequence interactions by opposite comb-shaped lines.]CC BY · PubMed Central
Figure 4. Experimental strategies for the identification of miRNA targets. MiRNA targets can be identified by comparisons of e.g. healthy vs. diseased cells or by downstream analysis upon experimental miRNA manipulations. Differential abundances of miRNAs and target mRNA are detectable by qPCR, microarray analyses, or next generation sequencing (NGS), differential levels of target proteins by western blot, immunostaining or mass spectrometry, direct interaction between miRNAs and their target mRNA by reporter assays or co-precipitation analyses, and down-stream miRNA effects by proliferation assays, viability assays or by assays tailored for specific miRNA regulated cell functions. [MiRNAs are indicated in red, target mRNAs in blue, and target proteins as blue spherical bodies. Interactions between miRNA and mRNA are depicted by opposite comb-shaped lines. Degradation of mRNA is indicated by dashed lines and reduction in protein expression by dashed outlines. Functional effects are symbolized by a grey shaded receptor icon. Ribosomes are shown as green bodies, RISCs as turquoise bodies.]
Figure 4. Experimental strategies for the identification of miRNA targets. MiRNA targets can be identified by comparisons of e.g. healthy vs. diseased cells or by downstream analysis upon experimental miRNA manipulations. Differential abundances of miRNAs and target mRNA are detectable by qPCR, microarray analyses, or next generation sequencing (NGS), differential levels of target proteins by western blot, immunostaining or mass spectrometry, direct interaction between miRNAs and their target mRNA by reporter assays or co-precipitation analyses, and down-stream miRNA effects by proliferation assays, viability assays or by assays tailored for specific miRNA regulated cell functions. [MiRNAs are indicated in red, target mRNAs in blue, and target proteins as blue spherical bodies. Interactions between miRNA and mRNA are depicted by opposite comb-shaped lines. Degradation of mRNA is indicated by dashed lines and reduction in protein expression by dashed outlines. Functional effects are symbolized by a grey shaded receptor icon. Ribosomes are shown as green bodies, RISCs as turquoise bodies.]CC BY · PubMed Central

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Metadata

Authors
Diener, C., Keller, A., & Meese, E.
Affiliations
  • Saarland University (USAAR), Institute of Human Genetics , 66421 Homburg , Germany
  • Saarland University (USAAR), Chair for Clinical Bioinformatics , 66123 Saarbrücken, Germany
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2023-11-30
Volume
52
Issue
4
Pages
1544-1557
ISSN
  • 0305-1048
  • 1362-4962
DOI
10.1093/nar/gkad1142
PMC
PMC10899768
Cited by
248
References
12
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Hans-und-Ruth-Giessen-Stiftung
  • Hedwig-Stalter-Stiftung

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