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Multiple Genetic Polymorphisms within microRNA Targets and Homologous microRNA-Binding Sites: Two More Factors Influencing microRNA-Mediated Regulation of Gene Expression

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Miruna Giurgiu, Robert Kaltenbach, Franziska Ahrend, Summer Weeks, Holly Clifton, Martin Bouldo, Vitaly Voloshin, Jiling Zhong, Siegfried Harden and Alexander Kofman

Submitted: 24 June 2023 Reviewed: 28 June 2023 Published: 14 August 2023

DOI: 10.5772/intechopen.1002250

Advances in Genetic Polymorphisms IntechOpen
Advances in Genetic Polymorphisms Edited by Nouha Bouayed Abdelmoula

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Advances in Genetic Polymorphisms

Nouha Bouayed Abdelmoula and Balkiss Abdelmoula

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Abstract

miRNA-mRNA interaction depends on multiple factors such as 3’UTR isoforms, the cell and tissue-specific expression levels of RNA-binding proteins, the sequence context around the mRNA target site, and other mechanisms. Genetic polymorphisms within miRNAs and their target sites appear to be among the most important ones because they influence the mode and outcome of miRNA-mRNA interaction universally and irreversibly. SNP disruption of miRNAs and their binding sites, as well as conformational changes preventing the access of the miRNA to its target site, are adopted as the most credible mechanistic explanations of SNP-mediated effects. The occurrence of multiple SNPs within the same miRNA-binding site implies their combinatorial mode of action. The presence of the repetitive (homologous) binding sites for the same miRNA on its mRNA target may both enhance the miRNA targeting and provide for the backup target site instead of the one disrupted by SNP, thus rescuing the miRNA functionality. While being underexplored, the multiple genetic polymorphisms within the miRNA-binding sites, as well as homologous miRNA-binding sites, may be considered as additional factors influencing miRNA-mediated regulation of gene expression.

Keywords

  • microRNA
  • mRNA
  • target
  • single-nucleotide polymorphism
  • homologous microRNA-binding sites

1. Introduction

Since the beginning of the 2000s, miRNAs stay in the focus of every aspect of medical and biomedical research [1, 2]. miRNAs are involved in a wide range of biological processes such as cell differentiation [3, 4, 5, 6, 7] and reprogramming [8], cellular senescence [9] and cell death [10, 11, 12, 13, 14, 15, 16], tissue and organ development [5, 17, 18, 19, 20] and regeneration [21, 22, 23, 24, 25, 26], cell signaling [27, 28], oxidative stress and metabolism [3, 29, 30, 31, 32, 33, 34, 35, 36, 37], mitochondrial dysfunctions [22, 38, 39], hormonal regulation [16, 40, 41] and adaptive responses [17], brain function [42, 43], inflammation [31, 44, 45, 46], immune response and the effects of the microbiome [46, 47, 48, 49, 50, 51, 52, 53], viral infections and latency [43, 54, 55, 56, 57, 58, 59, 60, 61], DNA damage and repair [22, 62, 63, 64, 65, 66, 67], genomic balance [68] and genomic instability [65, 69], etc.

miRNAs deregulation promotes the biological processes resulting in various human diseases [41, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84] including oncogenesis [6, 7, 35, 37, 54, 59, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120]. miRNAs are recognized as important factors that are involved in tumor cell invasiveness [121], metastases [90, 121, 122, 123, 124, 125, 126, 127, 128, 129], cancer cachexia [130], drug resistance [131, 132, 133, 134, 135, 136], sensitivity to chemotherapy [65, 137, 138], and radiosensitivity [138, 139, 140]. miRNAs are actively explored as both therapeutic agents [32, 112, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164] and targets [28, 42, 161, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174]. A growing number of reports point to the usefulness of miRNAs, and specifically circulating miRNAs [175, 176] as diagnostic and prognostic biomarkers [51, 70, 71, 73, 110, 112, 155, 160, 161, 174, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223] related to clinical and forensic [177, 224] studies, as well as normal physiological conditions, such as, diet [225] and increased physical activity [226, 227].

Deep sequencing and computational approaches indicate that miRNA genes comprise about 0.5–1% of the predicted genes in animals and humans [228]. One mRNA can be targeted by hundreds of miRNAs [84, 229], and a single miRNA can potentially recognize hundreds of different target transcripts [229, 230], which often share pathways to ensure their impact [52]. Therefore, miRNAs may be considered as global regulators of gene expression [231] with the vast targetome [52, 174] regulating about 90% of all protein-coding genes [232, 233, 234] and interactome-complex networking and cooperation between themselves [235, 236], as well as other regulatory molecules, in particular, transcription factors and noncoding RNAs [237, 238, 239].

Identification and characterization of the factors influencing miRNA functionality are essential to elucidate the mechanisms of miRNA activity and to explain and predict the effects of miRNAs for clinical applications. Genetic variations of both miRNAs and their target sites may have a significant impact on the efficacy of miRNA targeting. It is growingly recognized that naturally occurring variations in miRNAs and their target genes contribute to phenotypic complexity and may be associated with human pathologies [240, 241], including cancer [231, 242, 243, 244]. We present information about two underexplored SNP-related mechanisms influencing miRNA-mRNA interaction: the multiple SNPs within the single miRNA target site and the multiple (homologous) target sites for the same miRNA.

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2. miRNA properties and biogenesis

miRNAs belong to the category of small noncoding RNA molecules [2, 245] ranging between 19 and 24 nucleotides in length [229]. miRNAs have been detected in all biological species, including viruses [55, 56, 57, 58, 59, 60, 246]. Of note, bacteria do have short RNA sequences with the miRNA-similar functions, yet they are not considered as true miRNAs [247]. Bioinformatics analysis indicates the existence of miRNAs derived from transposable elements [248, 249]. Although miRNAs are usually located in the cytoplasm, several studies have detected a regulatory role of miRNAs in other cell compartments such as mitochondria (mitomiRs), nucleus, endoplasmic reticulum, granules, and P-bodies [38, 232]. Nuclear miRNAs participate in the regulation of miRNA biogenesis and function [250].

Circulating miRNA may be released by different types of cells and delivered into recipient cells for functional purposes, acting as cell-to-cell signaling mediators [251]. miRNA may be freed from dying cells or selectively sorted into the secreted small vesicles called exosomes [158, 229, 252, 253, 254, 255]. Such exosomal miRNAs are regarded as promising clinical biomarkers (see above). miRNA can undergo both vertical and horizontal transmissions among distinct species, remarkably through feeding between plants and animals [229, 245].

The biogenesis of canonical animal miRNAs starts with the transcription of the pri-miRNA by RNA Pol II [256, 257]. The pri-miRNA has the length of about several thousands of nucleotides [258], the 7-methylguanosine, and 3′- poly(A) tail [259]. The pri-miRNA forms a stem-loop structure, which is recognized and cleaved by Drosha (endonuclease RNAse III) and two molecules of its partner protein, DGCR8 (DiGeorge syndrome critical region 8, named Pasha in flies and nematodes), which results in the formation of pre-miRNA. The pre-miRNA is further processed by the Dicer (another endonuclease RNAse III). The Dicer’s partner protein TRBP (transactivation response element RNA-binding protein) is essential for miRNA processing in flies. The resulting short RNA duplex is associated with one of the AGO proteins to form the RISC, which is essential in destabilizing the target mRNA molecule or inhibiting its translation (for detailed review of miRNA biogenesis see [229, 260, 261, 262, 263]). Noncanonical miRNAs are produced without Drosha- or Dicer-catalyzed cleavage [84, 261, 264]. Each step of miRNA biogenesis is tightly regulated [260, 263]. Like all RNA molecules, miRNAs undergo posttranscriptional modifications, which may affect their properties [234, 260, 262, 265, 266]. Recent studies point to the existence of sequence variants in miRNAs called isomiRs, which differ from the annotated miRNAs by altered sequences due to the various posttranscriptional modifications [267, 268].

The core miRNA function is posttranscriptional regulation of the expression of targeted genes. It is achieved through miRNA-mediated RNA silencing [269]. miRNAs, as a part of the RISC, trigger the various forms of the translational repression of the target mRNA via blocking its ribosomal loading and initiation of translation, inhibiting translation elongation, and causing protein degradation [234, 261, 262]. It may also cause mRNA deadenylation and decay [234], which is typical for plants, whereas translational repression is more characteristic for animal cells [261, 270, 271]. In contrary to mRNA degradation, translational repression is reversible and can be employed for rapid response to internal or external cues [271].

While target repression is universally recognized as the dominant mode of miRNA action, some reports indicate that miRNAs can stabilize the targeted transcript [234, 272, 273, 274, 275, 276]. MiRNAs can also regulate gene expression both indirectly by targeting the mRNAs of transcription factors and directly after being transported back to the nucleus and binding to the complementary sequence in the promoter [232, 234, 250, 262, 276]. miRNAs can also perform other noncanonical functions acting as ligands for toll-like receptors [277].

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3. MiRNA target recognition

miRNAs bind to the complementary sequences of the host mRNA as a part of the RISC with its core component Ago proteins [229]. In plants, miRNAs show perfect or near-perfect complementarity to their target mRNA. In mammalian cells, as well as in other eukaryotes, miRNAs bind to mRNA sequences with imperfect complementarity [229, 278]. The 5′-end of miRNA exhibits the so-called seed sequence (Figure 1), which is complementary to six or more nucleotides at the 3’UTR of mRNA [2, 233, 262, 279].

Figure 1.

miRNA-mRNA interaction in animal cells (developed by F. Ahrend).

Canonical miRNA-binding sites are positioned in the 3’UTR of the targeted mRNA sequence and classified upon the extent and location of matching miRNA nucleotides: 6mers perfectly pair to nucleotides 2–7 on the 5′-end of miRNA, 7-merA1 and 7mer8—additional pairing with miRNA nucleotide 1 or 8 respectively, and 8mer sites match miRNA nucleotides 1–8 [261]. The efficacy of these sites is usually augmented by additional pairing at the 3′ end of miRNAs. In addition to the binding site at the miRNA 5′ end, pairing around the binding sites contributes to the targeting efficacy [233, 261, 280]. The so-called 3′-supplementary sites with atypical elaboration of the 6mer, 7mer, and 8mer sites (≥3–4 pairs), and 3′-compensatory sites stretching for more than 4–5 pairs, while the seed region is mismatched are called atypical sites [84, 233, 261]. The supplementary pairing is believed to enhance the miRNA-mRNA interaction with the greater specificity. However, in animal cells, the high complementarity beyond the seed may cause TDMD [281], the common mechanism of destabilization of the short RNA molecules including miRNAs, which is observed in many diseases [84]. In general, the miRNA-mRNA complementarity with nucleotides at 3′ end or with nucleotides in the center (centered pairing) in the absence of the perfectly matched seed nucleotides is believed to be much less effective in regulating gene expression [84, 233, 261, 282, 283, 284]. The noncanonical seed-matching sites may also be in the protein-coding regions of the target mRNAs and even in the 5’UTR mRNA sequence [84, 232, 233, 285, 286].

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4. Factors influencing miRNA targeting

miRNA-mRNA interaction depends on a range of factors. The posttranscriptional modification resulting in miRNA methylation causes structural changes that affect AGO binding [232]. miRNA sponges [287, 288, 289] bind miRNAs, thus preventing them from interacting with mRNA targets. miRNAs competition and cross talk with RNA-binding proteins [84, 232, 233, 236, 270], whose expression levels may depend on the cellular context and vary between the tissues [261, 290], also add up to the spectrum of various regulatory outcomes beside the dominating mechanism of miRNA targeting with moderate target repression [84]. miRNA targeting is known to depend on 3’UTR isoforms: 3’UTR size, alternative cleavage, and the location of target sequences within AU-rich regions [233, 261, 282, 284, 290, 291, 292].

The extent of complementary identity between miRNA and its mRNA targets appears to be one of the crucial factors, which determine the mode of target repression. The target cleavage by RISC is typical for plants, where the pairwise alignment is characterized by high complementarity. In opposite, the limited seed matching in animals often leads to translational inhibition [270]. It has been suggested that the above-mentioned noncanonical stabilization of the targeted transcript by miRNAs may depend on the complementarity between the miRNA and its target mRNA [275]. On the other hand, the extensive base-pairing may also cause TDMD [84, 293]. In this regard, genetic polymorphisms within miRNAs and their target sites appear to be among the most important mechanisms that ubiquitously and irreversibly define the mode and outcome of miRNA-mRNA interaction.

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5. miRNAs and genetic polymorphisms

SNPs are genetic variations (nucleotide substitutions and indels) in DNA sequence [294, 295]. SNPs within the mRNA noncoding regions do not change the protein sequence, but they may significantly alter gene expression by affecting transcription, RNA processing, translation, and interaction of mRNA with noncoding regulatory RNAs [296]. While most SNPs are likely to be functionally neutral, some of them may represent causative links with human diseases [297]. SNPs in miRNA-precursor flanking regions, promoters of miRNA-encoding genes, and in the genes involved in miRNA biogenesis (transcription and RNA processing) may result in higher or lower miRNA expression profiles [298, 299, 300, 301, 302], which, in turn, represent the unique disease-specific signatures that can identify cancer types [231, 240, 243, 303]. SNPs within mature miRNA sequences, specifically in their seed regions, dissimilarities in mature miRNAs due to variable cleavage sites for Drosha and Dicer [243, 301, 302, 304], and polymorphisms within or nearby miRNA-binding sites on genes targets, may enhance or weaken the interaction between miRNA and its target transcripts and contribute to phenotypic variations and disease susceptibility [230, 240, 241, 267, 294, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321].

Within the mRNA targets, SNPs can either create or destroy miRNA-binding sites. It may impair miRNA ability to target oncogenes and, in opposite, render tumor-suppressor genes susceptible to miRNA-mediated inhibition (Figure 2). SNPs located both within and beyond the seed-target regions [322] can affect miRNA-mRNA interaction by destabilizing the mRNA target molecule, slowing down its ability for ribosomal loading, and altering the secondary RNA structure, which in turn, may have an impact on the availability of miRNA-binding sites [284, 290, 323]. Disruption or creation of miRNA-binding sites is recognized as one of the most credible mechanistic explanations of SNP-mediated effects [240, 241].

Figure 2.

The hypothetical effects of SNP on miRNA-mRNA interaction and cancer development. 1a—miRNA suppresses the oncogenic mRNA, 1b—SNP disrupts the target site resulting in oncogene overexpression, 2a—miRNA does not control the expression of the tumor suppressor gene, and 2b—SNP creates the miRNA-binding site resulting in the inhibition of the tumor suppressor gene expression (developed by H. Clifton and F. Ahrend).

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6. Multiple SNPs within miRNA-binding sites

A considerable number of genome-wide association studies demonstrated links between the SNPs within the miRNA target sites and predisposition to various human diseases. The attention was mostly devoted to SNPs, whose population frequency was well above 1%. Still, miRNA target sites may harbor multiple SNPs, although most of them are of low population frequency [324]. Even though the probability of their coincidental occurrence within the site is low, the frequency of some SNPs may vary significantly due to their ethnic disparities [325]. It has been suggested that, at least for some genes, it is not a separately taken SNP, but the combinatorial effect of several SNPs that may determine the outcome and efficacy of miRNA-mediated regulation of gene expression [326]. The location of SNPs (seed-corresponding region, centered, or 3′ end position) should also be taken into consideration.

Thus, the presence of additional, even rare (low frequency) SNPs within miRNA target sites, may modify (weaken or enhance) the effects of the SNPs, which occur at higher frequencies. Consequently, multiple SNPs may increase the probability of the site disruption, but may be also neutral, and even enhancing (Figure 3). This situation is less typical for the protein-coding regions due to the selection pressure resulting in the fewer SNPs. In the case of the overlapping miRNA-binding sites, the outcome is less clear due to the co-targeting effect—additive repression by more than one miRNA [84, 232]. Beside this, the increased complementarity between miRNA and its target in animals may result in miRNA decay (see above about TDMD).

Figure 3.

The examples of disrupting, enhancing, and neutral SNPs within a single target site. The image shows the fragment of the human PDGFRA DNA sequence corresponding to the mRNA 3’UTR region, the miRNA-10a-5P binding site. 1—Enhancing through the formation of the G·U wobble base pair (rs1302330738), 2—Neutral switch from the G·U wobble base pair to the classical Watson-Crick G·C bond (rs1227726044), 3—Neutral switch from the G·U wobble base pair to the classical Watson-Crick A-T bond, 4—Neutral switch from the classical Watson-Crick G·C bond to the G·U wobble base pair (rs1322316972), 5—Disrupting (rs1724902856, rs1724902491, rs1314937650), and 6—Enhancing through the formation of the G·U wobble base pair (rs918309834). Note: The G·U wobble base pair has comparable thermodynamic stability to that of Watson-Crick base pairs and is known as a fundamental unit of RNA secondary structure in every class of RNA in organisms of all three phylogenetic domains [327]. However, it is still under the discussion whether G·U is characteristic for the canonical mRNA seed match [328] (developed by M. Giurgiu).

SNPs within the single target site may be independent (Figure 4) and mutually exclusive if they are overlapping (Figure 5). Of note, SNP frequencies in the databases reflect the experimental NextGen sequencing data, and the possible SNP overlap is not taken into consideration. If mutually exclusive SNPs are represented by the overlapping indel and nucleotide substitution, the latter one is “shadowed” by the indel (Figure 5), and its real population frequency may be higher than that presented in the database.

Figure 4.

The fragment of the human PDGFRA DNA sequence corresponding to the mRNA 3’UTR region, the miRNA-212-3P binding site. SNPs rs1577756917, rs1387790378, rs984854314, rs1560496903, and rs1454435576 represent independent events (developed by M. Giurgiu).

Figure 5.

The fragment of the human PDGFRA DNA sequence corresponding to the mRNA 3’UTR region, the miRNA-4444 binding site. SNPs rs1724893276 and rs1413062472, as well as rs1724893401, represent mutually exclusive events. rs1724893276 is an indel, and in the case of the deletion, neither rs1413062472 nor s172489 3401 (nucleotide substitutions) will be present (developed by M. Giurgiu).

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7. Homologous miRNA-binding sites

It has been reported that some mRNAs may have more than one binding (seed-matching) site for the miRNAs [329, 330, 331, 332, 333, 334, 335, 336]. These sites have the analogous seed-binding motif, but the different nucleotide content outside (Figure 6). Such multiple sites are proposed to act synergistically [330, 333, 334, 335, 337, 338], which, in turn, may depend on the distance between the sites [330, 338], as well as the activity and structural variations of miRNA-Ago complexes [336, 339]. It would be rational to suggest that if SNPs disrupt one of the miRNA-binding sites, the other sites for the same miRNA could preserve the miRNA-mediated control of gene expression. Such homologous miRNA-binding sites are present in almost all human genes, and their numbers are significant and directly proportional to the length of the 3’UTR [340].

Figure 6.

The repeated (homologous) target sites for miRNA-X (developed by A. Kofman).

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8. Bioinformatic tools

Whereas miRNAs and SNPs are both subjects of intense studies, there are few resources that allow to investigate the potential effects of SNPs on miRNA functionality.

PolymiRTS (Polymorphism in miRNAs and their Target Sites) is a database of naturally occurring DNA variations in miRNAs seed regions and miRNAs target genes [341]. PolymiRTS database was created by scanning 3’UTRs of mRNAs in humans and mice for SNPs in miRNA target sites. The database contains the results of genome-wide association studies about the links between the specific SNPs and human diseases. The PolymiRTS database also includes polymorphisms in target sites that have been supported by a variety of experimental methods and polymorphisms in miRNA seed regions.

MiRSNP is another database of human polymorphisms altering miRNA-binding sites [342]. It is a collection of 414,510 SNPs that are predicted to be able to affect (decrease/break or enhance/create) miRNA-mRNA binding.

MiRdSNP [343] is a database supplemented with the tools allowing the proximity searches between miRNA target sites and disease-associated SNPs (dSNPs) by gene name, miRbase ID, target prediction algorithm, disease, and any nucleotide distance between dSNPs and miRNA target sites. The web interface displays detailed sequence views showing the relationship among dSNPs, miRNA target sites, and SNPs. An interactive visualization tool shows the chromosomal distribution of dSNPs, miRNA target sites from TargetScan, and SNPs. The limitation of MiRdSNP is that the database contains only manually curated dSNPs on the 3’UTRs of human genes from available publications in PubMed, and the SNPs are only those that are disease-associated.

MSSD [344] is another manually curated database that provides comprehensive experimentally supported associations among miRNAs, SNPs, and human diseases. It has the same limitations as MiRdSNP.

miRNAhrend (https://franziskaahrend.pythonanywhere.com/) is the online-available package (beta version), which allows users to predict miRNA-target sites in any transcript upon the presence of seed-matching 6mers, which is verified by the complementarity-based alignment. The tool allows to assess how the presence of SNPs changes (“disappear/emerge”) the landscape of the target sites and their corresponding miRNAs, identify the homologous miRNA-binding sites, and track down the exact position of the sites within any studied RNA sequence.

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9. Conclusions

The ability of miRNAs to regulate the variety of genes in all tissues, as well as their presence in all biological species and their promise for clinical applications as novel diagnostics and therapeutics prompt further exploration of the factors influencing miRNA activity and functions. It is possible to assume that the presence of SNPs within miRNAs and their binding sites represents a powerful mechanism that can influence all biological processes in which miRNAs are involved. However, the growing number of reports indicates that the presence of SNPs cannot be interpreted as unalterable situation defining the biological outcome of miRNA targeting. The combinatorial effect of multiple SNPs located within the same target site, as well as beyond the target site, yet within the region where additional complementary matches between miRNA and its target can be formed, the circumstances where some SNPs may be mutually exclusive, and the homologous sites, which hypothetically can be utilized by miRNAs as an alternative target if the other sites are disrupted or become inaccessible, all these additional factors related to miRNA functionalities are anticipated of being studied with the development of the appropriate biocomputing tools and mathematical models.

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Abbreviations

miRNAmicroRNA
mRNAmessenger RNA
SNPsingle-nucleotide polymorphism
Polpolymerase
pri-miRNAprimary miRNA transcript
pre-miRNAprecursor miRNA
AGOargonaute proteins
RISCRNA-induced silencing complex
UTRuntranslated region
3′3-prime
5′5-prime
Indelinsertion/deletion
PDGFRAplatelet-derived growth factor receptor alpha
TDMDtarget-directed miRNA degradation

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Written By

Miruna Giurgiu, Robert Kaltenbach, Franziska Ahrend, Summer Weeks, Holly Clifton, Martin Bouldo, Vitaly Voloshin, Jiling Zhong, Siegfried Harden and Alexander Kofman

Submitted: 24 June 2023 Reviewed: 28 June 2023 Published: 14 August 2023

© The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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