MicroRNAs (miRNAs) are small, non-coding RNA molecules, typically 19 to 25 nucleotides in length, that play an important role in regulating gene expression. Unlike messenger RNAs (mRNAs) that carry genetic instructions for protein synthesis, miRNAs do not code for proteins. Their discovery, beginning in 1993 with the identification of the lin-4 gene in the nematode Caenorhabditis elegans, revealed their significant regulatory capabilities. Since then, numerous miRNAs have been identified across various life forms, from plants and viruses to humans, highlighting their widespread importance.
How MicroRNAs Regulate Genes
MicroRNA function begins with a process called biogenesis, where they are produced from longer RNA precursors. Initially, RNA polymerase II or III transcribes specific DNA regions into primary miRNAs (pri-miRNAs). These pri-miRNAs form characteristic stem-loop structures and are then processed in the cell nucleus by an enzyme complex containing Drosha and DGCR8. This processing yields precursor miRNAs (pre-miRNAs), which are subsequently transported from the nucleus to the cytoplasm.
Once in the cytoplasm, the pre-miRNAs undergo further processing by the enzyme Dicer, an RNase III endonuclease, which cleaves them into mature, double-stranded miRNA duplexes. One of the two strands from this duplex, known as the guide strand, is then incorporated into a multi-protein complex called the RNA-induced silencing complex (RISC). The RISC, guided by the miRNA, then locates messenger RNA (mRNA) molecules with complementary sequences, typically in their 3′ untranslated regions (3′-UTRs).
In animals, the binding between the miRNA and its target mRNA is often imperfect, meaning it does not require a perfect sequence match. This imperfect pairing allows a single miRNA to regulate multiple target mRNAs. The binding of the RISC to the mRNA then leads to two outcomes that inhibit protein production. One is the inhibition of protein translation, where the RISC complex physically blocks the cellular machinery responsible for synthesizing proteins from the mRNA. The second is the degradation of the mRNA molecule itself, making it unstable and prone to rapid breakdown. This dual mechanism reduces the amount of protein produced from a specific gene, regulating its expression.
MicroRNAs’ Diverse Roles in the Body
MicroRNAs influence a wide range of biological processes, guiding fundamental cellular activities. In development and differentiation, miRNAs help determine cell fate and orchestrate tissue and organ formation. Some miRNAs are expressed at specific developmental stages, ensuring precise timing of cellular transitions important for growth and maturation.
In the immune system, miRNAs are involved in the development, activation, and function of immune cells. They contribute to the fine-tuning of immune responses, helping the body distinguish between self and non-self, and regulating inflammatory processes.
MicroRNAs also affect metabolism, influencing pathways related to energy balance and nutrient processing. They impact how cells utilize glucose and fats, affecting overall metabolic health. For example, some miRNAs are linked to the regulation of lipid metabolism.
MiRNAs are also involved in regulating cell growth and programmed cell death, known as apoptosis. They can either promote or suppress cell proliferation, acting as important regulators in cell populations. This control is important for maintaining tissue homeostasis and preventing uncontrolled cell division.
MicroRNAs in Health and Disease
Dysregulation of microRNAs (expression levels too high or too low) can contribute to the development and progression of various human diseases. In cancer, miRNAs can act as either oncogenes (promoting cancer) or tumor suppressors (inhibiting cancer). For example, miR-21 is often overexpressed in many cancers, promoting cell proliferation, while miR-145 is frequently downregulated, suggesting a tumor-suppressive role. The miR-17-92 cluster and miR-155 have been identified as oncogenic miRNAs in certain lymphomas and leukemias.
Cardiovascular diseases also show implications of miRNA dysregulation. Specific miRNAs, such as miR-1 and miR-133a, are highly expressed in cardiac tissue and are important for heart development and function. Altered levels of these miRNAs are associated with conditions such as heart failure, myocardial infarction, and atherosclerosis.
Neurodegenerative disorders, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, also involve miRNA changes. For instance, miR-124 is downregulated in Alzheimer’s disease, contributing to amyloid-beta production. miRNAs are involved in neuronal development and plasticity, and their altered levels can affect neuronal survival and function.
Because miRNAs are stable in bodily fluids, they hold promise as biomarkers for disease diagnosis and prognosis. Changes in their circulating levels can indicate the presence of disease or predict its progression. Their stability also makes them attractive as potential therapeutic targets, leading to the development of miRNA mimics (to restore suppressed miRNA function) or inhibitors (to block overactive miRNAs).