MicroRNA
Small non-coding RNAs that regulate gene expression post-transcriptionally.
MicroRNA (miRNA, μRNA) are short, single-stranded RNA molecules, typically 21 to 23 nucleotides long, that do not code for proteins. They are found across a wide range of life forms, including plants, animals, and some viruses. Their main job is to silence other RNA molecules and regulate gene expression after transcription. They do this by binding to matching sequences on messenger RNA (mRNA) and then either cutting the mRNA in two, shortening its poly(A) tail to make it unstable, or blocking its translation into protein. In humans and other animals, the primary method is destabilizing the mRNA.
miRNAs are similar to small interfering RNAs (siRNAs) used in RNA interference, but they come from RNA transcripts that fold into short hairpin structures, whereas siRNAs come from longer stretches of double-stranded RNA. The human genome likely contains over 1,900 miRNA genes, though only about 500 are confirmed as genuine in the curated database MirGeneDB. These molecules are common in many mammalian cell types and are thought to target roughly 60% of human and other mammalian genes. Many miRNAs have been conserved through evolution, suggesting they serve critical biological roles. For instance, 90 miRNA families have remained unchanged since the last common ancestor of mammals and fish, and experiments where these genes are knocked out in mice often reveal essential functions.
The first miRNA was identified in the early 1990s, but they were not recognized as a distinct class of regulators until the early 2000s. In 1993, Victor Ambros’s group, with Lee and Feinbaum, discovered the lin-4 gene in the roundworm *C. elegans*. Instead of producing a protein-coding mRNA, lin-4 generated short non-coding RNAs, including one about 22 nucleotides long. This RNA had sequences partially complementary to the 3' UTR of the lin-14 mRNA, and it was proposed to block lin-14 translation. At the time, this was thought to be unique to nematodes. Simultaneously, Gary Ruvkun’s team, including Wightman and Ha, published work clarifying its mode of action. In 2000, a second small RNA, let-7, was found to repress lin-41 during later *C. elegans* development. Unlike lin-4, let-7 was conserved across many species, hinting that such “small temporal RNAs” might regulate development in diverse animals, including humans. A year later, lin-4 and let-7 were recognized as part of a large class
- discovery
- First miRNA discovered in 1993 by Victor Ambros's group
- nobel_prize
- 2024 Nobel Prize in Physiology or Medicine to Victor Ambros and Gary Ruvkun
- size
- 21–23 nucleotides
- function
- RNA silencing and post-transcriptional regulation of gene expression
- genome_estimate
- Over 1900 miRNAs in human genome; ~500 bona fide in MirGeneDB
- target_coverage
- Target about 60% of human and mammalian genes
Lore & Background
The first miRNA was discovered in 1993 by a group led by Victor Ambros, including Lee and Feinbaum, who isolated the lin-4 gene in C. elegans. Simultaneously, Gary Ruvkun's team, including Wightman and Ha, published work on its mode of action. The lin-4 gene produced short non-coding RNAs, one of which was a ~22-nucleotide RNA with sequences partially complementary to the 3' UTR of the lin-14 mRNA, proposed to inhibit translation. At the time, this was thought to be a nematode idiosyncrasy. In 2000, a second small RNA, let-7 RNA, was characterized, which represses lin-41 to promote a later developmental transition in C. elegans. The let-7 RNA was found conserved in many species, suggesting that small temporal RNAs might regulate development timing in diverse animals, including humans. A year later, lin-4 and let-7 were found to be part of a large class of small RNAs in C. elegans, Drosophila, and human cells, leading to the term 'microRNA' for this class.
Reader's Guide
MicroRNAs represent a fundamental layer of gene regulation, with broad implications for development, disease, and therapy. Their discovery, recognized by the 2024 Nobel Prize, revealed a previously unknown mechanism of post-transcriptional control. miRNAs are involved in RNA silencing and can target about 60% of human genes, often through seed region pairing. Aberrant miRNA expression is implicated in disease states, with the first human disease associated being chronic lymphocytic leukemia, where miRNAs act as both tumor suppressors and oncogenes. MiRNA-based therapies are under investigation. The biogenesis of miRNAs involves transcription by RNA polymerase II, processing from hairpin precursors, and sometimes RNA editing (isomiRs) that increases diversity. Nomenclature conventions distinguish mature forms (miR-), precursors (mir-), and species prefixes (e.g., hsa for human). The evolutionary conservation of many miRNA families underscores their importance, as knockout studies in mice have shown essential functions. The ability of a single miRNA to regulate hundreds of targets, often with mild repression, enables combinatorial regulation, a key feature in animals.
Did You Know?
- The first miRNA, lin-4, was discovered in 1993 in C. elegans and was initially thought to be a nematode idiosyncrasy.
- In 2024, American scientists Victor Ambros and Gary Ruvkun were awarded the Nobel Prize in Physiology or Medicine for discovering miRNA and its role in post-transcriptional gene regulation.
- About 6% of human miRNAs show RNA editing (isomiRs), producing sequences different from those encoded by DNA.
- The first human disease associated with miRNA deregulation was chronic lymphocytic leukemia, where miRNAs have a dual role as tumor suppressors and oncogenes.
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