microRNA : Special class Post-Transcriptional Regulators
MicroRNA is a class of post-transcriptional regulators. They are short ~22 nucleotide RNA sequences that bind to complementary sequences in the 3’ UTR of multiple target mRNAs, usually resulting in their silencing. MicroRNAs target ~60% of all genes, are abundantly present in all human cells and are able to repress hundreds of targets each.
Features of microRNA:
These features, coupled with their conservation in organisms ranging from the unicellular algae Chlamydomonas reinhardtii to mitochondria, suggest they are a vital part of genetic regulation with ancient origins.
MicroRNAs were first discovered in 1993 by Victor Ambros, Rosalind Lee and Rhonda Feinbaum during a study into development in the nematode Caenorhabditis Elegans (C. elegans) regarding the gene lin-14.
- This screen led to the discovery that the lin-14 was able to be regulated by a short RNA product from lin-4, a gene that transcribed a 61 nucleotide precursor that matured to a 22 nucleotide mature RNA which contained sequences partially complementary to multiple sequences in the 3’ UTR of the lin-14 mRNA.
- This complementarity was sufficient and necessary to inhibit the translation of lin-14 mRNA. Retrospectively, this was the first microRNA to be identified, though at the time Ambros et al speculated it to be a nematode idiosyncrasy.
- It was only in 2000 when let-7 was discovered to repress lin-41, lin-14, lin28, lin42 and daf12 mRNA during the transition in developmental stages in C. Elegans and that this function was phylogenetically conserved in species beyond nematodes, that it became apparent the short non-coding RNA identified in 1993 was part of a wider phenomenon.
- Since then over 4000 microRNAs have been discovered in all studied eukaryotes including mammals, fungi, and plants.
- More than 700 microRNAs have so far been identified in humans and over 800 more are predicted to exist.
- Comparing microRNAs between species can even be used to delineate molecular evolutionary history on the basis that the complexity of an organism’s phenotype may reflect that of the microRNA found in the genotype.
- When the human genome project mapped its first chromosome in 1999, it was predicted it would contain over 100,000 protein-coding genes.
- However, only around 20,000 were eventually identified (International Human Genome Sequencing Consortium, 2004) and for a long time, much of the non-protein-coding DNA was considered “junk”, though conventional wisdom holds that much if not most of the genome is functional.
- Since then, the advent of sophisticated bioinformatics approaches combined with genome tiling studies examining the transcriptome, systematic sequencing of full-length cDNA libraries and experimental validation (including the creation of microRNA derived antisense oligonucleotides called antagomirs) have revealed that many transcripts are for non-protein coding RNA of which many new classes have been deducted such as snoRNA and microRNA.
- Unfortunately, the rate of validation of micro RNA targets is substantially more time consuming than that of predicting sequences and targets.
- Due to their abundant presence and far-reaching potential, microRNAs have all sorts of functions in physiology, from cell differentiation, proliferation, apoptosis to the endocrine system, hematopoiesis, fat metabolism, limb morphogenesis.
- They display different expression profiles from tissue to tissue, reflecting the diversity of cellular phenotypes and as such suggest a role in tissue differentiation and maintenance.