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Posttranscriptional Upregulation by MicroRNAs

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Abstract MicroRNAs are small non‐coding RNA guide molecules that regulate gene expression via association with effector complexes and sequence‐specific recognition of target sites on other RNAs; misregulated microRNA expression and functions are linked to a variety of tumors, developmental disorders, and immune disease. MicroRNAs have primarily been demonstrated to mediate posttranscriptional downregulation of expression; translational repression, and deadenylation‐dependent decay of messages through partially complementary microRNA target sites in mRNA untranslated regions (UTRs). However, an emerging assortment of studies, discussed in this review, reveal that microRNAs and their associated protein complexes (microribonucleoproteins or microRNPs) can additionally function to posttranscriptionally stimulate gene expression by direct and indirect mechanisms. These reports indicate that microRNA‐mediated effects can be selective, regulated by the RNA sequence context, and associated with RNP factors and cellular conditions. Like repression, translation upregulation by microRNAs has been observed to range from fine‐tuning effects to significant alterations in expression. These studies uncover remarkable, new abilities of microRNAs and associated microRNPs in gene expression control and underscore the importance of regulation, in cis and trans, in directing appropriate microRNP responses. WIREs RNA 2012, 3:311–330. doi: 10.1002/wrna.121 This article is categorized under: Translation > Translation Mechanisms Translation > Translation Regulation Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action

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Posttranscriptional upregulation by microRNAs/microRNPs. The expression of a reporter bearing the test target site untranslated region (UTR) (Firefly luciferase with test UTR) is normalized to the expression of a transfection control reporter (Renilla luciferase) to exclude the effects of transfection efficiency and obtain the test‐UTR‐specific translation ratio. The ratio is further normalized against their RNA levels to obtain translation efficiency.20 The reference reporter translation efficiency (first and fourth gray bars of each graph) reads out the translation efficiency in the absence of the microRNA target site and provides basal translation levels (dashed blue line). Upregulated expression by microRNAs and microRNPs is observed as direct (activation) or indirect (relief of repression): (a) Activation: In comparison to the basal reference reporter translation efficiency (dashed blue line marking the translation of the first and fourth gray bars of each graph) as shown by a nontargeted or reference reporter, a targeted test reporter can be activated (orange bar with the change from basal reference reporter translation shown by the wide black arrow) when the translation efficiency is greater than that of the reference reporter translation (gray bars, dashed blue line). (b) Relief of repression: The test reporter translation can be repressed (red bar) where its translation is less than that of the reference reporter translation (gray bars, dashed blue line). When the regulatory effect of repression is abrogated, translation efficiency is increased (increase depicted by the wide black arrow) from repressed (red bar) to basal levels (pink bar comparable to the gray bars and dashed blue line depicting the reference reporter translation) because of the blocked repression. When the regulatory effect of activation (orange bar) is abrogated, the increased translation is lost and brought down to basal levels from activated levels (brown bar comparable to the gray bars and dashed blue line depicting the reference reporter translation) because of the blocked activation.

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Relief of repression of gene expression by microRNAs. Examples of microRNAs and specific target mRNAs demonstrating relief of microRNA‐mediated repression. (a) Relief of repression by target mRNA manipulation: influence of RNA‐binding proteins on the target site. Specific UTR‐RNA‐binding, regulatory proteins, such as HuR and DND1, can bind upstream or downstream of microRNA target sites in a regulated manner and influence the target site‐microRNP interaction, function, or alter the localization of the RNP, leading to alleviation of repression by the microRNP.26,27 (b) Relief of repression by decoy. Specific non‐coding RNAs such as pseudogene transcripts can relieve repression by decoying away distinct microRNAs via base pairing and functioning as decoy targets while specific factors can relieve repression by functioning as decoy AGO proteins. Non‐coding RNA: Non‐coding RNAs such as pseudogene transcripts PTENP1 and KRAS1P (depicted by a blue line base pairing with the microRNA), which bear similar sites to that found on the target PTEN and KRAS mRNAs are capable of binding and preventing microRNAs, miR19b, and miR20a from accessing their transcripts.152 Decoy by proteins/AGO10: Decoy proteins such as AGO10 in Arabidopsis is specifically expressed in shoot apical meristem to decoy miR166/165 away from the repressive AGO1 microRNP, thereby preventing repression of their targets, homeodomain leucine zipper transcription factor mRNAs, resulting in maintenance of undifferentiated shoot apical meristem.155 (c) Relief of repression by microRNP modification. The microRNP complex effector protein, AGO, as well as the microRNA may be modified to abrogate repression and thereby, permit expression. Stress‐induced modification of AGO: AGO proteins can be modified by poly‐ADP ribose (pADPr) as a stress response to conditions like amino acid starvation, glucose starvation, and anisomycin, leading to relocalization of AGO2 to the cytoplasm and decreased ability to associate with target sites and cause cleavage or repression.158 Mutant active LRRK2 in familial and sporadic Parkinson's disease and age‐related neuronal degeneration in Drosophila causes phosphorylation of 4E‐BP1 (p4EBP1), which associates more strongly with dAGO1 and hAGO2 and abrogates specific microRNA (let‐7 and miR184*)‐mediated repression.159 Uridylation of microRNAs: MicroRNAs modified at the 3′‐end, especially by uridylation, can lead to either altered stability of the microRNA or as in the case of miR26a/b, abrogate repression and mediate expression of target mRNAs such as IL‐6 mRNA.180

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Activation of gene expression by microRNAs. Examples of microRNAs and target mRNAs with target sites in the 5′‐ or 3′‐UTRs (untranslated regions) that demonstrate upregulated expression due to microRNA‐mediated activation. (a) Increased translation in response to cellular conditions. miR369‐3p and miR206 bind the 3′‐UTRs of and upregulate translation of TNFα and KLF4 mRNAs respectively in quiescent mammalian cell lines.30,56 FXR1‐iso‐a (FXR1a) and AGO2 are required for translation activation in G0 and in immature Xenopus laevis oocytes and are associated with the TNFα mRNA in G0 cells. XlmiR16 binds the 3′‐UTR and upregulates translation of Myt1 mRNA in immature Xenopus laevis oocytes.92 In proliferating cells, GW182 and AGO2 associate with target mRNAs and mediate repression. (b) Specific transcripts, microRNAs, and factors. Other specific microRNAs as well as specific factors can activate distinct transcripts with target sites in either the 5′‐UTR or the 3′‐UTR. 5′‐UTR: Liver specific miR122 stimulates translation of HCV RNA through direct binding to two target sites in the 5′‐UTR.134 miR346 interacts with the 5′‐UTR of RIP140 and upregulates translation in mouse brain tissue and p19 cells independent of AGO2.142 3′‐UTR: Binding of miR145 to the 3′‐UTR of myocardin mRNA increases its expression during smooth muscle development.29 Mmu‐miR34a/34b‐5p binds the 3′‐UTR and upregulates translation of an alternatively polyadenylated variant of β‐actin mRNA in mouse neuronal cells.143 Drosophila dAGO2 activates translation of m7G‐capped or A‐capped IRES‐containing 3′‐UTR target reporters lacking poly(A) tails in a Drosophila extract system.112 (c) Increased mRNA stability and translation. miR125b binding to the 3′‐UTR of κB‐Ras2 mRNA and miR466I binding to interleukin (IL)‐10 mRNA mediates increased mRNA stability in human macrophages.60,61 (d) MicroRNA‐mediated decoy. miR328 binds hnRNP‐E2 (hnRNPE2) and prevents it from repressing c/EBPα mRNA translation.145

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Posttranscriptional regulation in quiescent cells (G0 mammalian cells and G0‐like immature oocytes). G0 conditions not only demonstrate selective activation of G0 expressed mRNAs/microRNAs that are required for G0‐related functions but also display transcriptional and posttranscriptional downregulation113 especially of cell‐cycle factors and other such undesired genes,89,91 suggesting that other mRNAs, microRNAs, and regulatory RNA‐binding proteins downregulate gene expression of cell‐cycle factors88; both positive and negative regulation may collectively enable inhibition of the cell cycle and maintenance of the G0 state.89,91 (a) Translation upregulation of G0‐specific mRNAs/ microRNAs. GW182 is an essential component of the repressive microRNP complex regulated in G0.105–107 In conditions where GW182 interaction with AGO2 is restricted (oocytes, G0 cells, dAGO2), repression is abrogated.73,108,110–112 Under G0 conditions, FXR1‐iso‐a (FXR1a) can interact with the microRNP and alter its function to enable activation of specific, natural target mRNAs and of AGO2 or FXR1‐iso‐a tethered reporters. Activation of translation in quiescent conditions is observed with specific mRNAs such as tumor necrosis factor α (TNFα) and KLF4 in G0 mammalian cells, and Myt1 in immature Xenopus laevis oocytes mediated by specific microRNAs, miR369‐3p, miR206, and xlmiR16 respectively.30,56,92 (b) Downregulation of cell‐cycle mRNAs, maternal CPE‐bearing and other silenced mRNAs. Posttranscriptional downregulation by mechanisms including deadenylation113 is observed with cell‐cycle genes in G0 mammalian cells89,91 and with maternal mRNAs that are temporarily silenced in immature oocytes such as CPE‐bearing mRNAs in Xenopus laevis oocytes.9,10 These mechanisms may be mediated by UTR‐RNA‐binding regulatory proteins as observed in oocytes9,10 as well as potentially, by microRNA‐dependent mechanisms with or without collaboration with adjoining RNA‐binding protein sequences (RNABP site) and factors.

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