Cited by 5,287MicroRNA in disease regulationPlant Molecular Biology ResearchRNA Interference and Gene Delivery

The DOI matches its Crossref record; 144 of the 146 references it cites were found in a registry or an index; none of the 127 sources its claims cite is checked for support yet.

Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation

Open access
O'Brien, Jacob, Hayder, Heyam, Zayed, Yara, Peng, Chun·2018·Frontiers in Endocrinology

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.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes microRNA biogenesis, mechanisms of action, dynamic subcellular regulation, and extracellular circulation. It highlights miRNAs as both gene regulators and intercellular signals while noting unresolved questions about nuclear function, translational activation, and secretion/uptake.

Key findings

  • Canonical miRNA biogenesis involves pri-miRNA processing by Drosha/DGCR8, export by XPO5/RanGTP, Dicer cleavage into a mature duplex, and loading of the 5p or 3p strand into AGO1–4; non-canonical pathways include Drosha/DGCR8-independent mirtrons and m7G-capped pre-miRNAs, and Dicer-independent AGO2-dependent processing.
  • Most miRNAs bind 3′ UTR miRNA response elements to induce translational repression and mRNA deadenylation, decapping, and degradation via GW182, PAN2/3, CCR4-NOT, DCP2, and XRN1; binding to 5′ UTR/coding regions can silence, promoter binding can induce transcription, and activation occurs under specific conditions such as serum starvation, cell cycle arrest, oocytes, and amino acid starvation.
  • miRNA action is dynamic: miRISC localizes to rER, P-bodies, stress granules, endosomes, multivesicular bodies, mitochondria, and the nucleus; average polysome occupancy is below 40%, and FANTOM5 data indicate that the top five expressed miRNAs represent on average ~50% of the miRNA pool in a given human cell type, with about half cell-type enriched and one quarter broadly expressed.
  • Extracellular miRNAs are highly stable, resisting room-temperature degradation for up to 4 days and conditions such as boiling, freeze-thaw cycles, and high or low pH; they circulate in vesicles or bound to proteins such as AGO2, HDL, and NPM1, and can act as autocrine, paracrine, or endocrine signals, including via Toll-like receptors.

Methods

  • Narrative review; no primary experimental data, systematic search strategy, or sample size is reported.
  • The main analysis is a thematic synthesis of published literature on canonical and non-canonical biogenesis, miRNA-mediated gene regulation, subcellular dynamics, and extracellular miRNA circulation.
  • Data/sample: not applicable; the paper synthesizes prior studies and includes proposed models in figures.

Limitations

  • The paper states that understanding of when and how miRNAs regulate transcription is limited, conditions for translational activation need further exploration, and mechanisms of extracellular miRNA secretion and uptake are not well understood.
  • The paper notes that many studies use in vitro transfection into immortalized or cancer cell lines, which may not reflect endogenous miRNA functions in vivo, and that chemical tags on miRNAs could affect miRNA:MRE or AGO:miRNA interactions.
  • Evident from the text: as a narrative review, it does not systematically assess evidence quality or quantify effect sizes across the cited literature.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fendo.2018.00402

Cites

144 of 144 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Figures

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 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).CC BY · PubMed Central
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.
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.CC BY · PubMed Central

Verification

Claims the paper makes

82 Not checked yet · 18 Own interpretation · 6 No basis given · 1 Own method

Verify all 127 references — free account

Show all 65 claims

  • It may state two separate claims as one. 29
  • Probably not a substantial claim. 13
42 of 42
  • The paper relies on this without support.

    The first and last miRNA nucleotides clamp the miRNA within AGO proteins.

    “The first and last miRNA nucleotides clamp the miRNA within AGO proteins”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

2 of 2

Citations

Cites

Cited by

Sorted by citations

See all 5,287

Metadata

Authors
O'Brien, J., Hayder, H., Zayed, Y., & Peng, C.
Affiliations
York University (CA)
Corresponding author
Peng, Chun
Venue
Frontiers in Endocrinology
Published
2018-08-03
Volume
9
Pages
402-402
ISSN
1664-2392 (ISSN-L)
OpenAlex
W2811212358
Cited by
5,287
References
146
Citations by year
2026: 502 · 2025: 781 · 2024: 872 · 2023: 930 · 2022: 906 · 2021: 696 · 2020: 421 · 2019: 149 · 2018: 6
FWCI
33.05
Type
journal article
Language
en
Open access
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Canadian Institutes of Health Research (153146_1, MOP89931, 132565_1, 92222_1, MOP-81370)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
microRNA biogenesis, microRNA regulation of gene expression, 3' untranslated region, mRNA degradation, protein synthesis inhibition, Argonaute proteins, exosomes, extracellular miRNAs, intercellular communication

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-10-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review