MicroRNA-Mediated Gene Regulation in Mammalian Systems

MicroRNAs (miRNAs) are a class of small non-coding RNAs of approximately 22 nucleotides that orchestrate gene expression at multiple levels in mammalian cells. Arising from primary transcripts through sequential cleavage by the RNase III enzymes DROSHA and DICER, mature miRNAs are incorporated into Argonaute proteins to form the RNA-induced silencing complex (RISC). Canonically, miRNAs guide RISC to complementary sequences within the 3′ untranslated regions (UTRs) of target messenger RNAs (mRNAs), leading to translational repression or mRNA decay in the cytoplasm. Beyond this paradigm, miRNAs have been shown to localise to the nucleus, where they engage promoter or enhancer regions to modulate transcription and epigenetic states, a process referred to as transcriptional gene silencing or activation. These non-canonical activities involve interplay with chromatin modifiers and nascent transcripts, expanding the regulatory repertoire of miRNAs. Collectively, miRNA-mediated pathways control fundamental processes such as development, cellular differentiation, immune responses and tumourigenesis, with dysregulation implicated in a broad range of diseases. Emerging insights are unveiling the contextual factors—such as subcellular localisation of Argonaute proteins, availability of cofactors and cellular microenvironment—that fine-tune miRNA function, underscoring their significance as biomarkers and therapeutic targets in mammalian biology.

Research from Nature Portfolio

Recent studies have advanced the conceptual framework of miRNA action by illuminating nuclear dimensions of post-transcriptional silencing. One foundational work has demonstrated that the nucleoplasmic protein Sfpq binds long 3′ UTRs of specific transcripts to foster aggregation of miRISC components, thereby enhancing the precision of miRNA targeting. This Sfpq-dependent mechanism operates in both nuclear and cytoplasmic compartments, extending the influence of miRNAs to nascent transcripts and revealing a layer of regulatory complexity that integrates RNA-binding proteins with miRNA-mediated gene silencing.

MicroRNA-Mediated Gene Regulation in Mammalian Systems publication trend

The graph below shows the total number of articles in microrna-mediated gene regulation in mammalian systems across all publications each year (not limited to Nature Index journals).

Technical terms

microRNA (miRNA): Small non-coding RNA of ~22 nucleotides that regulates gene expression.

Argonaute: Core protein component of the RNA-induced silencing complex that binds miRNAs.

RNA-induced silencing complex (RISC): Ribonucleoprotein assembly that mediates miRNA-guided target recognition.

3′ untranslated region (3′ UTR): Non-coding segment at the end of mRNA where miRNAs often bind.

Transcriptional gene silencing (TGS): Repression of gene transcription mediated by small RNAs and chromatin modifiers.

Post-transcriptional gene silencing (PTGS): Inhibition of mRNA translation or stability after transcription by small RNAs.

References

1. Nuclear localization of Argonaute 2 is affected by cell density and may relieve repression by microRNAs. Nucleic Acids Research (2023).
2. Nuclear miR-451a activates KDM7A and leads to cetuximab resistance in head and neck squamous cell carcinoma. Cellular and Molecular Life Sciences (2024).
3. MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions. International Journal of Molecular Sciences (2016).
4. Nuclear functions of mammalian MicroRNAs in gene regulation, immunity and cancer. Molecular Cancer (2018).
5. Post-transcriptional gene silencing mediated by microRNAs is controlled by nucleoplasmic Sfpq. Nature Communications (2017).