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The Non-Canonical Aspects of MicroRNAs: Many Roads to Gene Regulation - PubMed

  • ️Tue Jan 01 2019

Review

The Non-Canonical Aspects of MicroRNAs: Many Roads to Gene Regulation

Christiaan J Stavast et al. Cells. 2019.

Abstract

MicroRNAs (miRNAs) are critical regulators of gene expression. As miRNAs are frequently deregulated in many human diseases, including cancer and immunological disorders, it is important to understand their biological functions. Typically, miRNA-encoding genes are transcribed by RNA Polymerase II and generate primary transcripts that are processed by RNase III-endonucleases DROSHA and DICER into small RNAs of approximately 21 nucleotides. All miRNAs are loaded into Argonaute proteins in the RNA-induced silencing complex (RISC) and act as post-transcriptional regulators by binding to the 3'- untranslated region (UTR) of mRNAs. This seed-dependent miRNA binding inhibits the translation and/or promotes the degradation of mRNA targets. Surprisingly, recent data presents evidence for a target-mediated decay mechanism that controls the level of specific miRNAs. In addition, several non-canonical miRNA-containing genes have been recently described and unexpected functions of miRNAs have been identified. For instance, several miRNAs are located in the nucleus, where they are involved in the transcriptional activation or silencing of target genes. These epigenetic modifiers are recruited by RISC and guided by miRNAs to specific loci in the genome. Here, we will review non-canonical aspects of miRNA biology, including novel regulators of miRNA expression and functions of miRNAs in the nucleus.

Keywords: MicroRNAs; biogenesis; non-canonical; nuclear localization; transcriptional regulation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Biogenesis of microRNAs (miRNAs). (A) Canonical miRNA biogenesis starts with transcription of miRNA genes by RNA Polymerase II (POL II) or POL III. Next, the primary (pri)-miRNAs are processed by DROSHA/DiGeorge syndrome critical region 8 (DGCR8). The resulting pre-miRNAs are exported to the cytoplasm by Exportin-5 (XPO-5). MiRtrons are spliced out and the intron lariat is debranched by lariat debranching enzyme 1 (DBR1), which results in pre-miRNAs. Once exported, the pre-miRNAs are cleaved by DICER/trans-activation-responsive RNA binding protein (TRBP). Next, the passenger strand is degraded by the component 3 promoter of RNA-induced silencing complex (C3PO) complex. The guide strand, which is loaded into RNA-induced silencing complex (RISC), is involved in translational repression and subsequent transcript degradation. (B) MiR-451 is processed in a DICER-independent manner. After processing by DROSHA/DGCR8 and export to the cytoplasm, the passenger strand is degraded by Argonaute 2 (AGO2)-mediated cleavage and trimming. (C) Non-canonical processing of small nucleolar RNAs (snoRNAs) results in snoRNA-derived RNAs (sdRNAs). SnoRNAs are spliced from genes and debranched by DBR1. Subsequently, snoRNAs are exported to the cytoplasm by an unknown mechanism and are processed by DICER into sdRNAs which are loaded in RISC. (D) Non-canonical processing of transfer RNAs (tRNAs) results in tRNA-derived miRNAs. (1) After transcription, tRNAs are transported to the cytoplasm by XPO-5 or XPO-T. The 5′-loop and the 3′-loop is cleaved by DICER, resulting in 5′-tRNA-derived RNA (tDR)-fragments and 3′-tDR-fragments respectively. The anticodon loop is cleaved by Angiogenin (ANG), resulting in 5′-tRNA stress-induced fragments (tiRNAs). All tDR-fragmentss are subsequently loaded into RISC similar to canonical miRNAs. (2) After transcription, tRNAs can be stabilized by Lupus autoantigen (LA) and exported to the cytoplasm by XPO-T. LA inhibits the processing of tRNAs by DICER and preserves tRNA stability for translation. HSP90: heat shock-Protein 90, TNRC6A: trinucleotide repeat-containing gene 6A.

Figure 2
Figure 2

Nuclear localization mechanisms of miRNAs. (A) After canonical processing of pri-miRNAs, miRNAs containing specific motifs are transported back into the nucleus by still unknown RNA-binding proteins (RBPs) and mechanisms. (B) After processing by DROSHA/DGCR8, pre-miRNAs will be processed by nuclear DICER/TRBP for (1) degradation or (2) RISC loading in the nucleus by heterogeneous nuclear ribonucleoprotein D (HNRPD) or human antigen R (HuR), which both shuttle between the cytoplasm and the nucleus by an unknown mechanism. (C) After processing by DROSHA/DGCR8, miRNAs bind to XPO-5 and will be exported trough the nuclear pore complex (NPC). Mature miRNAs bound by AGO2 will be imported back into the nucleus by DICER and Importin 8 (IPO8). TNRC6A will be imported into the nucleus by Karyopherin β1 (KPNB1). Subsequently, RISC will be assembled in the nucleus and will interact with miRNA targets, which allows for miRNA enrichment in the nucleus. Ultimately, AGO2 and TNRC6A will be exported back to the nucleus by XPO1.

Figure 3
Figure 3

MiRNA-mediated transcriptional regulation is shown in three steps. (A) (1) In steady state, POL II will transcribe promoter RNAs (pRNAs) in promoter regions and enhancer RNAs (eRNAs) in enhancer regions. (2) MiRNA-loaded AGO1 can interact with promoter DNA. MiRNA-loaded AGO2 can bind to pRNAs, which recruits WD repeat-containing protein 5 (WDR5) to the promoter, or to eRNAs which recruits P300 to the enhancer region. (3) The interaction of AGO1 with promoter regions causes POL II and histone H3 Lysine 4 trimethylation (H3K4me3) enrichment on the promoter. The interaction of AGO2 with pRNAs causes WDR5 and POL II enrichment on promoters, which leads to a decrease in histone H3 Lysine 27 trimethylation (H3K27me3) and increase in histone H4 acetylation (H4Ac) levels, accompanied by an increase in pRNA transcription. The interaction of AGO2 with eRNAs causes enrichment of P300 and POL II on enhancer regions, an increase of local histone H3 Lysine 27 acetylaction (H3K27Ac) and histone H3 Lysine 4 monomethylation (H3K4me1) levels, a decrease of H3K27me3 levels and an increase of eRNA expression. These processes ultimately lead to increased gene expression. (B) MiRNAs are involved in transcriptional gene silencing, which are depicted in three steps. (1) In steady state, POL II will be enriched on promoter regions, resulting in gene transcription. (2a) MiRNA-loaded AGO1/DICER complex interacts with promoter regions. (2b) MiRNA-loaded AGO2/TNRC6A-complex interacts with promoter regions. (2c) MiRNA-loaded AGO2 interacts with the promoter region, and prevents POL II binding to the promoter. (2d) MiRNA-loaded AGO2 binds to pRNAs. (3a) MiRNA-loaded AGO1/DICER complex interacts with the promoter region and recruits Yin Yang 1 (YY1), which results in increased H3K27me3 levels. (3b) MiRNA-loaded AGO2 recruits histone methyltransferases (HMTs) to increase H3K9me2 and H3K27me3 levels. (3c) MiRNA-loaded AGO2 recruits DNA-methyltransferase 3B (DNMT3B) to methylate CpGs in the genome and silences gene expression. (3d) MiRNA-loaded AGO2/TNRC6A complex recruits the CCR4-NOT complex to degrade POL II-derived transcripts. These processes will ultimately lead to transcriptional gene silencing.

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