MicroRNAs (miRNAs) are small, non-coding RNA molecules, typically measuring between 21 and 25 nucleotides in length. Unlike messenger RNA (mRNA), which carries the blueprint for building proteins, miRNAs do not contain instructions for protein synthesis. Instead, they function as master regulators of gene expression. Their discovery in the early 1990s revealed a fundamental mechanism by which cells fine-tune the amount of protein produced from various genes.
The Molecular Mechanism of Regulation
MicroRNAs exert their influence through post-transcriptional gene silencing, which occurs after the genetic code has been transcribed into mRNA. The mature, single-stranded miRNA acts as a guide, directing the RNA-Induced Silencing Complex (RISC) to specific target mRNA sequences. The RISC complex is the functional executioner of the silencing process.
The miRNA guides the RISC to a complementary sequence, most often found in the 3′ untranslated region of the target mRNA. The degree of complementarity determines the resulting action. If the pairing is imperfect, the RISC complex represses the translation of the mRNA, blocking the cellular machinery from turning the message into a protein.
If the pairing is nearly perfect, the RISC complex induces the physical degradation of the target mRNA molecule. A single miRNA can bind to and regulate hundreds of different mRNA targets, creating highly intricate regulatory networks that control cellular function.
Essential Biological Roles
MicroRNAs are deeply involved in maintaining normal physiological balance. They are implicated in cellular differentiation, the process by which an unspecialized stem cell develops into a specific cell type, such as a neuron or a muscle cell. This control ensures appropriate gene expression during development and tissue maintenance.
MicroRNAs also manage the immune system, acting as a rheostat to balance response and tolerance. For example, miR-155 is upregulated in activated T-cells, promoting a strong immune response, while miR-146a acts as a negative feedback loop to dampen inflammation.
Control also extends to metabolism, where miRNAs coordinate the body’s response to nutrient availability. In the pancreas, miR-375 regulates insulin secretion from beta cells, impacting glucose homeostasis. In the liver, miR-33b influences the expression of enzymes involved in gluconeogenesis, regulating glucose production.
Link to Disease and Dysfunction
When microRNA expression or function becomes aberrant, the regulatory networks they govern are disrupted, leading to the development or progression of various human diseases. In cancer, miRNAs are classified as either tumor suppressors or oncogenic factors. Tumor-suppressing miRNAs, such as miR-34a, are frequently downregulated in malignant cells.
This allows their targets—oncogenes like MYC and BCL-2—to be overproduced, driving uncontrolled cell growth. Conversely, oncogenic miRNAs are overexpressed and silence genes that would normally suppress tumor formation.
Dysregulation is also a factor in cardiovascular disease, where the miR-29 family is often downregulated, contributing to the excessive deposition of collagen and subsequent cardiac fibrosis. In neurodegenerative disorders, microRNA changes are linked to the pathology of conditions like Alzheimer’s disease. Downregulation of the miR-29 family in the brain is associated with increased production of the enzyme BACE-1, which generates the toxic amyloid-beta plaques characteristic of the disease. Additionally, miR-132 shows decreased expression in the Alzheimer’s brain and is linked to the accumulation of hyperphosphorylated Tau protein.
MicroRNA as Diagnostic and Therapeutic Tools
The involvement of miRNAs in disease pathology has positioned them as promising candidates for clinical application, both as diagnostic biomarkers and as therapeutic agents. MicroRNAs are remarkably stable in bodily fluids, including blood, urine, and saliva, because they are protected from degradation by being packaged within microvesicles or bound to the RISC complex. This stability allows them to be reliably measured, making them excellent, non-invasive biomarkers for early disease detection and monitoring. In the therapeutic field, two primary strategies are under investigation to restore healthy gene regulation.
miRNA Mimics
For diseases where a tumor-suppressing miRNA is deficient, “miRNA mimics” are synthetic, double-stranded RNAs designed to replicate the function of the missing endogenous miRNA.
Antagomirs
Conversely, to treat conditions caused by an overactive, oncogenic miRNA, researchers utilize “antagomirs.” These are chemically modified antisense oligonucleotides that bind to and neutralize the harmful miRNA, preventing it from silencing its target genes and allowing the production of beneficial proteins.