MicroRNA Biogenesis Mechanisms in Eukaryotic Systems

MicroRNAs (miRNAs) are short (~22 nucleotides) non-coding RNAs that direct sequence-specific silencing of target messenger RNAs via Argonaute-associated effector complexes. In the canonical pathway, miRNA genes are transcribed as primary transcripts (pri-miRNAs) by RNA polymerase II, then processed in the nucleus by the Microprocessor complex—comprising Drosha and DGCR8—into hairpin precursors (pre-miRNAs). These pre-miRNAs are exported to the cytoplasm by Exportin-5, where Dicer cleaves the hairpins to generate miRNA duplexes. One strand is loaded into the RNA-induced silencing complex (RISC) to guide target recognition and repression. Non-canonical routes augment this core machinery: mirtrons arise from spliced introns that fold into pre-miRNA-like hairpins, while agotrons are short introns that bypass Dicer entirely by associating directly with Argonaute proteins. Additional variants employ splicing-dependent tail removal or exosome-mediated trimming. Collectively, these diverse biogenesis mechanisms broaden the regulatory scope of miRNAs, shaping developmental programmes, stress responses and disease processes across eukaryotes.

Research from Nature Portfolio

Recent studies have uncovered a novel class of Argonaute-associated short introns, termed agotrons, which evade Dicer processing yet repress target mRNAs by directly loading onto Argonaute proteins. Detailed structural analyses revealed that agotrons comprise 80–100 nucleotide introns that fold into stable hairpins, leading to conserved silencing activity across mammalian species. Parallel work in the major histocompatibility complex (MHC) has identified numerous haplotype-specific miRNA transcripts within non-coding regions, many of which undergo Dicer-dependent maturation and map within linkage disequilibrium blocks harbouring disease-associated variants. These findings suggest that polymorphic miRNAs contribute to immune regulation and disease susceptibility. In addition, investigation of a mammalian-specific mirtron, miR-1224, demonstrated its role in promoting endothelial tube formation by targeting an anti-angiogenic adaptor protein, thereby modulating VEGF and Notch signalling. Together, these discoveries illuminate previously unrecognised biogenesis pathways and functional specialisations of non-canonical miRNAs in health and disease.

MicroRNA Biogenesis Mechanisms in Eukaryotic Systems publication trend

The graph below shows the total number of articles in microrna biogenesis mechanisms in eukaryotic systems across all publications each year (not limited to Nature Index journals).

Technical terms

Microprocessor complex: The nuclear ribonuclease complex composed of Drosha and DGCR8 that cleaves pri-miRNAs into pre-miRNAs.

Drosha: An RNase III enzyme that, with its partner DGCR8, initiates canonical miRNA processing in the nucleus.

Dicer: A cytoplasmic RNase III enzyme that cleaves pre-miRNA hairpins to produce miRNA duplexes.

Exportin-5: A nuclear transport receptor that exports pre-miRNAs from the nucleus to the cytoplasm.

Argonaute: The core protein family of the RNA-induced silencing complex that binds mature miRNAs to guide mRNA repression.

RISC (RNA-induced silencing complex): The effector complex, centred on Argonaute, that mediates miRNA-guided gene silencing.

Mirtron: A non-canonical miRNA precursor generated from spliced introns that form pre-miRNA hairpins without Drosha processing.

Agotron: A subclass of short introns that bypass both Drosha and Dicer, directly associating with Argonaute to regulate target RNAs.

Pri-miRNA: The primary miRNA transcript containing one or more hairpin structures processed by the Microprocessor.

Pre-miRNA: The hairpin precursor cleaved from pri-miRNA, exported to the cytoplasm and further processed by Dicer.

References

1. A tailed mirtron promotes longevity in Drosophila. Nucleic Acids Research (2023).
2. Argonaute-associated short introns are a novel class of gene regulators. Nature Communications (2016).
3. Mirtronic miR-4646-5p promotes gastric cancer metastasis by regulating ABHD16A and metabolite lysophosphatidylserines. Cell Death & Differentiation (2021).
4. Analysis of Nearly One Thousand Mammalian Mirtrons Reveals Novel Features of Dicer Substrates. PLOS Computational Biology (2015).
5. Novel and Haplotype Specific MicroRNAs Encoded by the Major Histocompatibility Complex. Scientific Reports (2018).
6. A mammalian mirtron miR-1224 promotes tube-formation of human primary endothelial cells by targeting anti-angiogenic factor epsin2. Scientific Reports (2017).