microRNAs: Definition & Overview
MicroRNAs (miRNAs) are small, RNA molecules encoded in the genomes of plants and animals (Figure 1). These highly conserved, ~21-mer RNAs regulate the expression of genes by binding to the 3'-untranslated regions (3'-UTR) of specific mRNAs.
Although the first published description of an miRNA appeared ten years ago (Lee 1993), only in the last two to three years has the breadth and diversity of this class of small, regulatory RNAs been appreciated. A great deal of effort has gone into understanding how, when, and where miRNAs are produced and function in cells, tissues, and organisms. Each miRNA is thought to regulate multiple genes, and since hundreds of miRNA genes are predicted to be present in higher eukaryotes (Lim 2003b) the potential regulatory circuitry afforded by miRNA is enormous. Several research groups have provided evidence that miRNAs may act as key regulators of processes as diverse as early development (Reinhart 2000), cell proliferation and cell death (Brennecke 2003), apoptosis and fat metabolism (Xu 2003), and cell differentiation (Dostie 2003, Chen 2003). Recent studies of miRNA expression implicate miRNAs in brain development (Krichevsky 2003), chronic lymphocytic leukemia (Calin 2004), colonic adenocarcinoma (Michael 2003), Burkitt’s Lymphoma (Metzler 2004), and viral infection (Pfeffer 2004) suggesting possible links between miRNAs and viral disease, neurodevelopment, and cancer. There is speculation that in higher eukaryotes, the role of miRNAs in regulating gene expression could be as important as that of transcription factors.
Figure 1. Transcription of miRNAs. Approximately 60% of miRNAs are expressed independently, 15% of miRNAs are expressed in clusters, and 25% are in introns.
Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM (2003) bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113: 25-36.
Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM (2004) Human miRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Natl. Acad. Sci. USA. 101: 2999-3004.
Chen X. (2003) A MicroRNA as a Translational Repressor of APETALA2 in Arabidopsis Flower Development. Science E-Pub.
Dostie J, Mourelatos Z, Yang M, Sharma A, Dreyfuss G. (2003) Numerous microRNPs in neuronal cells containing novel microRNAs. RNA 9(2): 180-6. Erratum in: RNA 9(5): 631-2.
Krichevsky AM, King KS, Donahue CP, Khrapko K, Kosik KS (2003) A miRNA array reveals extensive regulation of miRNAs during brain development. RNA 9: 1274-1281.
Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75: 843-854.
Lim LP, Glasner ME, Yekta S, Burge CB, Bartel DP (2003b) Vertebrate microRNA genes. Science 299: 1540.
Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A. (2004) High expression of precursor miRNA-155/BIC RNA in children with Burkitt lymphoma. Genes Chromosomes Cancer 2: 167-169.
Michael MZ, O’Connor SM, van Holst Pellekaan NG, Young GP, James RJ (2003) Reduced accumulation of specific microRNAs in colorectal neoplasia. Molecular Cancer Research 1: 882-91.
Pfeffer S, Zavolan M, Grasser FA, Chien M, Russo JJ, Ju J, John B, Enright AJ, Marks D, Sander C, Tuschl T. (2004) Identification of virus-encoded microRNAs. Science 304(5671): 734-6.
Reinhart BJ, Slack FA, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AC, Horvitz HR, and G Ruvkun. (2000) The 21 nucleotide let-7 RNA regulates C. elegans developmental timing. Nature 403: 901–906.
Xu P, Vernooy SY, Guo M, Hay BA. (2003) The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism. Curr Biol 13(9): 790-5.