miRNAs are short RNA molecules of ∼22-nt in length that play important roles in post-transcriptional control of gene expression. miRNAs normally function as negative regulators of mRNA expression by binding complementary sequences in the 3′-UTR of target mRNAs and causing translational repression and/or target degradation. Much research has been undertaken to enhance understanding of the biogenesis, function and targeting of miRNAs. However, until recently, the mechanisms underlying the regulation of the levels of mature miRNAs themselves have been largely overlooked. Although it has generally been assumed that miRNAs are stable molecules, recent evidence indicates that the stability of specific mature miRNAs can be regulated during key cellular and developmental processes in certain cell types. Here we discuss the current knowledge of the mechanisms by which mature miRNAs are regulated in the cell and the factors that contribute to the control of their stability.

Introduction

miRNAs are key factors in the post-transcriptional control of gene expression and play a critical role in many cellular processes, as well as being implicated in human disease [13]. Post-transcriptional regulation of mRNAs is critical to maintain the correct balance of proteins within cells, with RNA degradation shown to be essential for correct growth and development in many organisms [47]. miRNAs mainly function by binding to complementary sequences within the UTRs of their target mRNAs, resulting in translational repression and/or degradation of the target mRNA and therefore less protein product. However, some studies have also shown that miRNAs are able to promote translation of their targets [811], resulting in increased production of proteins from such mRNAs. miRNAs may act alone or in combination with other miRNAs; the 3′-UTRs of some mRNAs are predicted to include binding sites for many miRNAs, which may act co-operatively or competitively with each other [12,13].

The levels of a particular miRNAs in relation to their targets are likely to be critical in this post-transcriptional control. The amount of a particular miRNA within a cell is related to its rate of biogenesis (including its transcription), as well as its rate of degradation. The biogenesis of miRNAs begins with their transcription as longer precursors (pri-miRNAs) followed by processing by factors, such as Drosha, to stem loop structures known as pre-miRNAs [14]. These pre-miRNAs are then cleaved by further factors such as Dicer to generate mature 21–22-nt miRNAs, from both the 5′ (5p) and the 3′ (3p) ends of the pre-miRNA stem loop [15].

Although much work has been performed to investigate the regulation of miRNA biogenesis in terms of the processing of the primary transcripts into pre- and mature miRNAs, the stability of the mature miRNAs has been largely overlooked. Since their discovery, miRNAs have been thought to be one of the most stable forms of RNA. However, in recent years, many studies have shown that miRNA stability can vary depending on developmental and cellular context. It is therefore of great interest to identify the regulatory mechanisms and the enzymes responsible for the regulation of mature miRNAs.

miRNAs vary in their stability

miRNAs have long been thought to be one of the more stable members of the RNA family. A study using dicer1 knockout mouse embryonic fibroblasts estimated the average half-life of miRNAs to be 119 h [16], suggesting miRNAs are up to 10 times more stable than their mRNA counterparts. For example miR-125b was shown to have a half-life of 225 h, illustrating how stable some mature miRNAs can be [16]. However, the roles of miRNAs as switches in critical developmental processes, such as developmental timing [17] and tissue growth [18], indicate that the stability of miRNAs can be shorter under certain cellular conditions. Indeed, the miR-16 family of miRNAs have been shown to be heavily regulated during cell cycle re-entry in mouse fibroblasts. When a cell re-enters G1 from G0, miR-503 and miR-10a decrease, with miR-503 showing a half-life of only 3.6 h [19]. Similarly, miR-29b is maintained at a low level during all stages except during mitosis, when its level increases dramatically due to enhanced stability rather than increased transcription [20]. Moreover, miRNAs have been shown to be rapidly turned over in mouse neuronal cells, where levels of the miR-183/96/182 cluster, along with miR-204 and miR-211, are rapidly down-regulated within 3 h during dark adaptation in retinal neurons [21]. The observed down-regulation was shown to be a result of an increase in miRNA decay; however, the exoribonuclease responsible for this decay remains unknown.

It is therefore clear that although miRNAs may normally be more stable than their mRNA counterparts, there are specific developmental and cellular conditions which require miRNAs to be rapidly turned over. How this switch occurs and the mechanisms by which they are removed will be discussed below.

Multiple factors contribute to the stability of a miRNA

Nucleotide additions to miRNAs

A number of studies have uncovered a neat mechanism for miRNA regulation through nucleotide additions to their 3′-ends (Table 1) [2227]. 3′-Adenylation has been shown to affect miRNA stability, as the poly(A) polymerase GLD2 (PAPD4 (poly(A) polymerase-associated domain containing 4)) selectively adds a single adenosine residue to the 3′-end of miR-122 resulting in the stabilization of the miRNA in the liver [26]. GLD2-mediated 3′-adenylation has additionally been shown to reduce activity of miRNAs in mouse liver and human hepatoma Huh7 cells without affecting stability [27]. In addition to GLD2, the enzymes MTPAP (mitochondrial poly(A) polymerase), PAPOLG (poly(A) polymerase gamma) and TUT1 (terminal uridyl transferase 1) have also been demonstrated to be involved in miRNA 3′-tailing in human cells [25,27]. Interestingly, knockdown of the uridyl transferases ZCCHC11 (zinc finger, CCHC domain containing 11) and ZCCHC6 (zinc finger, CCHC domain containing 6) results in an increase in miRNA adenylation, though the impact of this remains unclear [24].

Table 1
miRNA modifications and their effects on miRNA activity
miRNA Modification Enzyme responsible Effect on miRNA Reference 
miR-26 Uridylation ZCCHC11 Inhibition of miR-26 activity [23
miR-122 Adenylation GLD2 Stabilization of miR-122 in the liver [26
miR-26a, miR-27 Adenylation GLD2 Reduces miRNA activity [27
let7, miR-10, miR-99/100 and miR-196, miR-125 and miR-26 families Uridylation ZCCHC11/6 activity stimulated by GUAG and UUGA motifs No change in stability as Knockdown of ZCCHC11/6 does not affect miRNA abundance [24
miR-126-5p and miR-379 Uridylation ZCCHC11 Reduction in IGF-1 silencing activity [22
miRNA Modification Enzyme responsible Effect on miRNA Reference 
miR-26 Uridylation ZCCHC11 Inhibition of miR-26 activity [23
miR-122 Adenylation GLD2 Stabilization of miR-122 in the liver [26
miR-26a, miR-27 Adenylation GLD2 Reduces miRNA activity [27
let7, miR-10, miR-99/100 and miR-196, miR-125 and miR-26 families Uridylation ZCCHC11/6 activity stimulated by GUAG and UUGA motifs No change in stability as Knockdown of ZCCHC11/6 does not affect miRNA abundance [24
miR-126-5p and miR-379 Uridylation ZCCHC11 Reduction in IGF-1 silencing activity [22

In addition to adenylation, 3′-uridylation of miRNAs has been observed. Uridylation has historically been known to play a role in signalling histone RNAs for degradation [28,29], but has more recently also been shown to affect miRNA activity, rather than miRNA stability. For example, miR-26, which plays a role in the regulation of cytokine signalling through negative regulation of interleukin 6 (IL6) expression, is uridylated by the terminal nucleotidyl transferase ZCCHC11 in human (A549) and mouse (MLE-15) cell lines. This inhibits miR-26 activity which in turn enhances IL6 expression [23]. Other studies have shown a role for uridylation by the nucleotidyl transferases ZCCHC11 and ZCCHC6 in development as knockdown of ZCCHC11/6 homologues in zebrafish result in developmental defects due to aberrant expression of specific developmentally important miRNAs that are predicted to target Hox genes [24].

As well as nt tailing, 2′-O methylation by Hen1 (small RNA 2′-O-methyltransferase) at the 3′-termini of Drosophila miRNAs has been shown to be a protective feature that increases miRNA stability, at least partially through the inhibition of 3′-tailing by nucleotidyl transferases [30]. Additionally, in Drosophila S2 cells half of the miR-277 pool was modified at the 3′-terminus; modification that was significantly reduced following Hen1 knockdown and was dependent upon and argonaute 2 (Ago2). This mechanism of miRNA modification demonstrates specificity to miR-277 as another miRNA, bantam, showed no 3′-methylation [31]. 3′-Methylation of miRNAs has also been shown to aid Ago loading, which in turn may also protect miRNAs from degradation [32,33].

Destabilizing elements within mature miRNAs

In addition to nucleotide additions to the mature miRNA sequences, intrinsic sequences that affect miRNA stability have also been identified [19,34,35]. AU rich elements are known to be involved in mRNA turnover [36,37] and miRNAs containing high AU/UA dinucleotide densities show the shortest half lives in primary human neuronal cells implicating an effect of AU sequences on miRNA stability [35]. Other examples of specific nucleotide affecting miRNA stability also exist, such as the instability of miR-503 in mouse fibroblasts, which is dependent upon the seed region and nucleotides in the 3′-end [19]. Changes in the seed region may affect other mechanisms of regulating miRNA stability such as target-mediated degradation (discussed further below). miR-382 in human embryonic kidney (HEK)293 cells presents another example, as specific sequences at positions 16–22 control its stability [34]. Therefore, it appears that certain miRNAs carry elements within their short sequence to allow for their regulation.

Table 2
Exoribonucleases known to affect mature miRNA stability
Nuclease miRNA Organism/Context Reference 
XRN2 let-7c C. elegans [54
XRN1 miR-382 Human HEK293 cells [30,34,52
 miR-277 D. melanogaster*, Drosophila S2 cells.  
XRN1–DCS1 complex let-7, miR-57, miR-59, miR-235, miR-241 C. elegans [53
Dis3 miR-252 D. melanogaster [6
Rrp41 (exosome) miR-382 Human HEK293 cells [34
PNP miR-211 Human HO-1 cells [55
Eri1 Unspecified but general increase in miRNA abundance observed Human natural killer and CD4+ T-cells [56
Nuclease miRNA Organism/Context Reference 
XRN2 let-7c C. elegans [54
XRN1 miR-382 Human HEK293 cells [30,34,52
 miR-277 D. melanogaster*, Drosophila S2 cells.  
XRN1–DCS1 complex let-7, miR-57, miR-59, miR-235, miR-241 C. elegans [53
Dis3 miR-252 D. melanogaster [6
Rrp41 (exosome) miR-382 Human HEK293 cells [34
PNP miR-211 Human HO-1 cells [55
Eri1 Unspecified but general increase in miRNA abundance observed Human natural killer and CD4+ T-cells [56

*Study by Jones et al. indicates a role for XRN1 (5′-3′ exoribonuclease 1) in miR-277 regulation but not through degradation of mature miR-277 [52].

miRNA protection by RNA-binding proteins

In addition to performing direct modifications to the miRNA, RNA-binding proteins also play roles in regulating the stability of miRNAs. For example, GW182 is involved in miRNA stabilization through binding to Ago proteins, which are members of the RNA-induced silencing complex (RISC). Knockdown of GW182 results in destabilization of miR-146a and miR-155, largely due to their degradation by Rrp41 (exosome complex exonuclease rrp41)-dependent 3′-5′ exoribonucleolytic decay [38]. Like GW182, Ago2 has been found to protect miRNAs from degradation in mouse embryonic fibroblasts [39,40], in which the stabilities of miR-21, miR-16, miR-20a, miR-92 and let-7a were significantly reduced following Ago2 knockdown. Overexpression of Ago2 enhanced the stability of the miRNAs tested with the stabilizing effect independent of its catalytic activity, indicating the Ago2–miRNA interaction is the stabilizing factor. In corroboration of this, an earlier study also showed that loss of Ago2 leads to a decrease in levels of a number of mature miRNAs [39]. Stabilization in both cases is probably due to the inaccessibility of the 5′ and 3′-termini of the Ago2/GW182 bound miRNAs to nucleases and/or 3′-tailing enzymes. In addition to the RISC-associated proteins, Translin, an RNA-binding protein previously not known to have a role in miRNA regulation, has been shown to bind miR-122a in mouse testes leading to increased stability [41].

The fate of a miRNA following target association

miRNA–RISC binding to their targets usually results in either translational repression and/or degradation of the RNA target. However, the fate of the target-bound miRNA is unclear. A few contrasting studies have shown that miRNA-target association can result in both stabilization and destabilization of the miRNA [30,42,43]. In Drosophila, promotion of miRNA decay has been observed when extensive complementarity exists between miRNAs and their targets, such as in cell lines expressing egfp mRNA with completely complementary miRNA-binding sites [30]. The majority of Ago-bound miRNAs contain a single non-template 3′-uracil residue; it could be that this 3′-tailing in the presence of high complementarity promotes the degradation of the miRNAs in a similar way to the 3′-tailing methods mentioned above. In addition to target-mediated degradation of let-7, bantam and miR-34 in Drosophila [30]; high complementarity-driven target-mediated degradation was also observed for miR-223 in human cells [42], where perfect binding of miR-223 to its target results in a reduction in miR-223 expression. A further study showed similar findings with miRNA degradation following association with highly complementary targets in primary rodent neurones [43].

In contrast with target-mediated destabilization of miRNAs, work in Caenorhabditis elegans has provided examples of target-mediated protection of miRNAs [44]. Target association prevents the release of the miRNA from the RISC resulting in its stabilization. It is proposed that this may be a mechanism by which strand selection from the miRNA duplex occurs in that the desired miRNA binds to RISC whereas the partner strand is left accessible to degradation. This mechanism of target-mediated protection has only been reported in C. elegans, therefore it would be of interest to see if a similar mechanism exists in other eukaryotes. The balance between target-mediated protection and degradation appears be dependent upon the level of complementarity between a miRNA and its target; high complementarity results in miRNA degradation whereas weaker target–miRNA association results in stabilization. This would coincide with the generally accepted theory that it is the extent of complementarity which determines whether miRNA–target association results in translational repression or degradation of the target mRNA.

Non-coding RNAs control miRNA abundance

In addition to binding with mRNAs, miRNAs may also bind to complementary non-coding RNAs (ncRNAs) which then act as natural miRNA sponges [45,46], sequestering specific miRNAs and resulting in an overall reduction in the pool of miRNAs able to regulate their targets. Circular ncRNAs, who are themselves resistant to degradation, have been shown to down-regulate miRNAs in this way [47,48]. For example, a circular RNA containing multiple conserved miR-7-binding sites that functions as a miR-7 antagonist has been identified in human cells, whereas another circular RNA (Sry), which may function as a miR-138 sponge, has been found in the mouse testes [47]. Animal genomes have been shown to express many circular RNAs [48], raising the possibility that many of these naturally occurring RNAs could act as a mechanism to fine tune the expression of numerous miRNAs, adding yet another level of complexity to their post-transcriptional regulation.

A similar mechanism used by viruses to evade host miRNA activity has also been identified [49]. The Herpesvirus saimiri genome encodes ncRNAs containing complementary-binding sites for the key anti-viral miRNA miR-27. miR-27 binds to these ncRNAs and is degraded, enhancing viral survival [49]. In a similar mechanism, murine cytomegalovirus expresses the transcript m169 which acts as a decoy site for miR-27a/b resulting in down-regulation and allowing viral replication [50]. A further study identified down-regulation of the miR-17 family during human cytomegalovirus (HCMV) infection. HCMV express an ncRNA containing binding sites for multiple members of the miR-17 family resulting in their sequestration and subsequently enhancing virus production [51].

Degradation of mature miRNAs by exoribonucleases

Recent studies have aimed to identify the ribonucleases responsible for the degradation of specific miRNAs (Table 2). Identification of these enzymes is key to the understanding of how miRNA stability is regulated and has been somewhat neglected. The 5′-3′ pathway of RNA decay has been implicated in the decay of a selection of miRNAs [34,5254]. For example, in C. elegans, the nuclear 5′-3′ exoribonuclease XRN2 is responsible for the clearance of the key developmental miRNA let-7 [54]. This activity was shown to be specific to the mature let-7 as loss of xrn-2 resulted in no change in the stability of the precursor, pre-let-7. It is interesting that a nuclear exoribonuclease is able to specifically regulate a substrate that is thought to be present in the cytoplasm, although miRNAs such as miR-29b, which contain a hexanucleotide sequence directing nuclear import, have been observed in the nucleus [20]. Additionally the cytoplasmic 5′-3′ exoribonuclease XRN1 (5′-3′ exoribonuclease) was shown to have a modest effect of the stability of miR-382 in human cells [34]. Furthermore, work in Drosophila melanogaster identified a role for the XRN1 orthologue, Pacman, in the regulation of miR-277 expression [52]. A possible mechanism by which XRN1 is recruited to miRNA targets is through an interaction with the decapping scavenger enzyme DCS-1 (decapping scavenger enzyme 1) [53]. C. elegans mutant in dcs-1 show a general increase in miRNA levels whereas DCS-1 and XRN1 co-immunoprecipitate, thus identifying a potential miRNA degradation complex that is required for the degradation of miRNAs released from the RISC but is independent of the normal scavenging activity of DCS-1 [53].

In addition to the 5′-3′ pathway, the 3′-5′ degradation pathway has also been observed to play a part in the regulation of miRNA stability. In the study on miR-382 described above, knockdown of the exosome component Rrp41 in HEK293 cells resulted in stabilization of miR-382, although the catalytic exoribonuclease responsible for this degradation was not identified [34]. However, in Drosophila wing imaginal discs, Dis3 (defective in sister chromatid disjoining 3), a catalytic component of the exosome, has been identified as the ribonuclease responsible for the regulation of a small subset of miRNAs [6]. This study used RNA-seq in a global analysis of miRNA levels to show that the mature miR-252-5p (rather than the pre-miRNA) is increased in Dis3 knockdown cells suggesting that Dis3 directly targets this miRNA for degradation. Another exoribonuclease, the interferon (IFN)-inducible 3′-5′ exoribonuclease polynucleotide phosphorylase (PNP) has been shown to target miR-221 for degradation in the human HO-1 cell line [55]. Similar to the findings in Drosophila, only a small subset of miRNAs appear to be sensitive to PNP regulation. Finally, the 3′-5′ exoribonuclease ERI1 (3′-5′ exoribonuclease 1) has been implicated in negatively regulating miRNA expression as natural killer and CD4+ T-cells mutant for Eri1 showed a significant increase in global miRNA abundance [56]. Therefore, exoribonucleases in both the 5′-3′ and the 3′-5′ pathways appear to be responsible for selective degradation of miRNAs.

Concluding remarks

Thus far we have only scratched the surface of the regulation of miRNA stability. There are a variety of mechanisms that appear to be specific to the cellular and developmental context; these occur as both cis- and trans-acting factors that allow great diversity over the control of miRNA expression (Figure 1). The expression of miRNAs themselves, like their mRNA targets, can be tightly regulated as the cellular and developmental circumstances require. It appears that 3′-tailing or intrinsic destabilization elements play a role in targeting miRNAs for degradation. The outstanding question concerns the mechanisms whereby these destabilization elements recruit decay machinery and the identification of the ribonucleases responsible for the degradation of particular miRNAs under specific cellular conditions. Further work is therefore required to characterize the mechanisms used to target miRNAs for degradation as well as the ribonuclease complexes involved.

Cartoon depicting the factors which affect miRNA degradation

Figure 1
Cartoon depicting the factors which affect miRNA degradation

(A) Mature miRNAs have been identified to be degraded by exoribonucleases such as the XRN1/2 family and members of the exosome. (B) High complementarity between a miRNA and its target(s) can result in destabilization of the mature miRNA termed target-mediated miRNA destabilization (TMMD). The mechanisms by which the mature miRNAs become available for decay and how high complementarity stimulates miRNA decay remain unknown. (C) Alternatively, lower complementarity of miRNA-target association has been shown to result in stabilization of mature miRNAs through protecting the miRNA sequence from exoribonucleases. (D) RNA-binding proteins such as Ago2 (shown), GW182 and Translin associate with and protect miRNAs from exoribonucleolytic decay through making the 3′- and 5′-ends of the miRNA inaccessible to exoribonucleases.

Figure 1
Cartoon depicting the factors which affect miRNA degradation

(A) Mature miRNAs have been identified to be degraded by exoribonucleases such as the XRN1/2 family and members of the exosome. (B) High complementarity between a miRNA and its target(s) can result in destabilization of the mature miRNA termed target-mediated miRNA destabilization (TMMD). The mechanisms by which the mature miRNAs become available for decay and how high complementarity stimulates miRNA decay remain unknown. (C) Alternatively, lower complementarity of miRNA-target association has been shown to result in stabilization of mature miRNAs through protecting the miRNA sequence from exoribonucleases. (D) RNA-binding proteins such as Ago2 (shown), GW182 and Translin associate with and protect miRNAs from exoribonucleolytic decay through making the 3′- and 5′-ends of the miRNA inaccessible to exoribonucleases.

Funding

This work was funded by a Brighton and Sussex Medical School studentship [grant number WC003-11]; and the Biotechnology and Biological Sciences Research Council [grant number BB/I021345/1].

Abbreviations

     
  • Ago2

    argonaute 2

  •  
  • Dis3

    defective in sister chromatid disjoining 3

  •  
  • HCMV

    human cytomegalovirus

  •  
  • HEK

    human embryonic kidney

  •  
  • IL6

    interleukin 6

  •  
  • ncRNA

    non-coding RNA

  •  
  • nt

    nucleotide

  •  
  • PNP

    polynucleotide phosphorylase

  •  
  • RISC

    RNA-induced silencing complex

  •  
  • XRN1

    5′-3′ exoribonuclease 1

  •  
  • ZCCHC6

    zinc finger, CCHC domain containing 6

  •  
  • ZCCHC11

    zinc finger, CCHC domain containing 11

Translation UK 2015: Held at the University of Aberdeen, U.K., 7–9 July 2015.

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