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Review
. 2018 Aug 3:9:402.
doi: 10.3389/fendo.2018.00402. eCollection 2018.

Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation

Jacob O'Brien  1 , Heyam Hayder  1 , Yara Zayed  1 , Chun Peng  1
Affiliations
Review

Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation

Jacob O'Brien et al. Front Endocrinol (Lausanne). .

Abstract

MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in regulating gene expression. The majority of miRNAs are transcribed from DNA sequences into primary miRNAs and processed into precursor miRNAs, and finally mature miRNAs. In most cases, miRNAs interact with the 3' untranslated region (3' UTR) of target mRNAs to induce mRNA degradation and translational repression. However, interaction of miRNAs with other regions, including the 5' UTR, coding sequence, and gene promoters, have also been reported. Under certain conditions, miRNAs can also activate translation or regulate transcription. The interaction of miRNAs with their target genes is dynamic and dependent on many factors, such as subcellular location of miRNAs, the abundancy of miRNAs and target mRNAs, and the affinity of miRNA-mRNA interactions. miRNAs can be secreted into extracellular fluids and transported to target cells via vesicles, such as exosomes, or by binding to proteins, including Argonautes. Extracellular miRNAs function as chemical messengers to mediate cell-cell communication. In this review, we provide an update on canonical and non-canonical miRNA biogenesis pathways and various mechanisms underlying miRNA-mediated gene regulations. We also summarize the current knowledge of the dynamics of miRNA action and of the secretion, transfer, and uptake of extracellular miRNAs.

Keywords: cell-cell communication; extracellular microRNA; gene regulation; microRNA biogenesis; microRNA dynamics.

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Figures

Figure 1
Figure 1
MicroRNA biogenesis and mechanism of action. Canonical miRNA biogenesis begins with the generation of the pri-miRNA transcript. The microprocessor complex, comprised of Drosha and DiGeorge Syndrome Critical Region 8 (DGCR8), cleaves the pri-miRNA to produce the precursor-miRNA (pre-miRNA). The pre-miRNA is exported to the cytoplasm in an Exportin5/RanGTP-dependent manner and processed to produce the mature miRNA duplex. Finally, either the 5p or 3p strands of the mature miRNA duplex is loaded into the Argonaute (AGO) family of proteins to form a miRNA-induced silencing complex (miRISC). In the non-canonical pathways, small hairpin RNA (shRNA) are initially cleaved by the microprocessor complex and exported to the cytoplasm via Exportin5/RanGTP. They are further processed via AGO2-dependent, but Dicer-independent, cleavage. Mirtrons and 7-methylguanine capped (m7G)-pre-miRNA are dependent on Dicer to complete their cytoplasmic maturation, but they differ in their nucleocytoplasmic shuttling. Mirtrons are exported via Exportin5/RanGTP while m7G-pre-miRNA are exported via Exportin1. All pathways ultimately lead to a functional miRISC complex. In most cases, miRISC binds to target mRNAs to induce translational inhibition, most likely by interfering with the eIF4F complex. Next, GW182 family proteins bound to Argonaute recruit the poly(A)-deadenylases PAN2/3 and CCR4-NOT. PAN2/3 initiates deadenylation while the CCR4-NOT complex completes the process, leading to removal of the m7G cap on target mRNA by the decapping complex. Decapped mRNA may then undergo 5′−3′ degradation via the exoribonuclease XRN1. Modified from Hayder et al. (26).
Figure 2
Figure 2
Proposed model of miRNA localization and function. miRISC has been detected in several subcellular locations. In the nucleus, miRISC is enriched at sites of active transcription where it can interact with DNA to promote active or inactive chromatin states. It can also interact with nascent mRNA to promote more efficient splicing or alternate splicing profiles. miRISC can interact with nuclear messenger ribonucleoprotein (mRNP) to promote its degradation or remain in A miRISC:mRNP complex as it is shuttled out of the nucleus. Cytoplasmic miRISC can diffuse throughout the cytosol or undergo shuttling, most likely via microtubules. Within the cytosol, miRISC can associate with polysomes, inhibit translation initiation, mediate mRNA decay, or promote translational activation. On the rough endoplasmic reticulum, miRISC can interact with translating mRNA to inhibit translation. Furthermore, unbound miRISC can also accumulate on the rER to interact with newly rER-bound mRNA. Rough ER miRISC:mRNP complexes that are translationally inhibited can shuttle to the early/late endosomes to complete mRNA deadenylation and decay. miRISC can then be recycled into the cytosol or shuttled to the lysosome for degradation. miRISC may also localize to transient, membrane-free processing bodies where it can mediate target mRNA translational inhibition and storage or decay. Under certain cellular conditions, miRISC:mRNPs may be shuttled to stress granules for storage and/or degradation. miRISC can also localize to the mitochondria to promote translational activation or mRNA translational inhibition and decay. Localization of miRISC within the Golgi is likely from vesicles secreted from the early endosome. Moreover, endocytosed miRISC may be shuttled to the Golgi or recycled into the cytosol. Lastly, vesicular or vesicle-free miRISC can be exocytosed from at least the late endosome into the extracellular milieu to mediate cell-cell communication.
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References

    1. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell (1993) 75:843–54. 10.1016/0092-8674(93)90529-Y - DOI - PubMed
    1. Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell (1993) 75:855–62. 10.1016/0092-8674(93)90530-4 - DOI - PubMed
    1. Horvitz HR, Sulston JE. Isolation and genetic characterization of cell-lineage mutants of the nematode Caenorhabditis elegans. Genetics (1980) 96:435–54. - PMC - PubMed
    1. Chalfie M, Horvitz HR, Sulston JE. Mutations that lead to reiterations in the cell lineages of C. Elegans. Cell (1981) 24:59–69. 10.1016/0092-8674(81)90501-8 - DOI - PubMed
    1. Ambros V, Horvitz HR. The lin-14 locus of Caenorhabditis elegans controls the time of expression of specific postembryonic developmental events. Genes Dev. (1987) 1:398–414. 10.1101/gad.1.4.398 - DOI - PubMed