Micro ribonucleic acids (microRNAs or miRNAs) are small, non-coding RNA molecules that operate within the cell. These molecules are 19 to 24 nucleotides in length, too short to contain instructions for protein production. Their discovery overturned the view that RNA’s only function was to serve as a messenger between DNA and protein synthesis.
Instead, microRNAs function as precise regulators of gene expression, acting like molecular dimmer switches that fine-tune the amount of protein produced by a gene. This regulatory role was first uncovered in the early 1990s in the roundworm Caenorhabditis elegans, establishing that small, non-coding RNAs are a fundamental component of the genetic machinery.
The Molecular Machinery
The creation of a functional microRNA molecule, known as biogenesis, begins in the cell’s nucleus with the transcription of a long primary transcript (pri-miRNA). This long RNA forms a distinctive hairpin structure, recognized by the Microprocessor complex. This complex includes the ribonuclease Drosha and its partner DGCR8.
Drosha cleaves the pri-miRNA to release a shorter precursor molecule (pre-miRNA). The pre-miRNA is then exported from the nucleus into the cytoplasm by a transporter protein.
Once in the cytoplasm, the ribonuclease Dicer recognizes the hairpin and cuts the loop off the molecule. This results in a short, double-stranded microRNA duplex. Only one strand of this duplex becomes the mature, functional microRNA, which is then incorporated into the RNA-Induced Silencing Complex (RISC) to seek out its target messenger RNA.
How MicroRNAs Regulate Genes
The mature microRNA strand guides the RISC complex to specific messenger RNA (mRNA) transcripts in the cytoplasm. The Argonaute protein within RISC performs the gene silencing action. The microRNA directs Argonaute using a sequence of nucleotides that must partially or fully match a sequence on the target mRNA, usually in the 3′ untranslated region (3’UTR).
This binding leads to post-transcriptional regulation, stopping the genetic message from being translated into a protein. The outcome depends on the degree of complementarity. If the microRNA achieves an almost perfect match, Argonaute will cleave and degrade the mRNA transcript entirely.
If the match is only partial, the binding blocks the cellular machinery responsible for translation. By repressing translation, the ribosome cannot synthesize a protein, reducing the gene’s output without eliminating the mRNA transcript.
Role in Disease and Health
Because microRNAs regulate the expression of hundreds of genes, disruption to their normal activity contributes to human diseases. When a microRNA is overexpressed or its function is lost, gene expression is disturbed. This dysregulation is particularly evident in cancer, where microRNAs function as either tumor suppressors or oncogenes.
Cancer
The let-7 microRNA family functions as a tumor suppressor by repressing genes that promote cell proliferation. Abnormally low let-7 levels lead to uncontrolled cell growth and tumor formation. Conversely, some microRNAs, such as the miR-17-92 cluster, act as oncogenes. Their overexpression suppresses the action of tumor-fighting genes.
Cardiovascular and Neurodegenerative Disease
MicroRNA dysregulation is also implicated in cardiovascular disease and neurodegeneration. In the heart, specific microRNAs are linked to cardiac remodeling after injury; for example, miR-21 promotes fibrosis, which impairs heart function. In neurodegenerative conditions like Alzheimer’s disease, members of the miR-15/107 family are abnormally regulated, potentially affecting brain cell function.
MicroRNAs as Tools in Medicine
The stability of microRNAs in body fluids and their link to disease makes them promising candidates for medical applications. One developing area is their use as non-invasive biomarkers for early disease detection. Circulating microRNAs can be measured in accessible samples like blood, serum, or urine, offering a molecular snapshot of the patient’s tissues.
Specific microRNA signatures can signal the presence of diseases such as cancer or cardiovascular stress before symptoms appear, providing a new diagnostic tool. Distinguishing between disease subtypes based on a microRNA profile is also useful for personalized medicine.
Researchers are also exploring therapeutic strategies to correct microRNA dysregulation, involving either restoring lost function or blocking harmful activity. To restore function, synthetic microRNA mimics can replace missing tumor-suppressor microRNAs. Conversely, to block an overactive oncogenic microRNA, researchers use inhibitors called antagomirs, which are modified RNA molecules designed to bind to and neutralize the harmful microRNA.