MicroRNA biogenesis.
Based on Wienholds and Plasterk,
FEBS Letters 2005, 579: 5911-5922. |
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| What are microRNAs? |
microRNAs - novel modulators of gene expression
MicroRNAs (miRNAs) have rapidly emerged as an important class of short endogenous RNAs that act as post-transcriptional regulators of gene expression by base-pairing with their target mRNAs. The 19-25 nucleotide (nt) mature miRNAs are processed sequentially from longer hairpin transcripts by the RNAse III ribonucleases Drosha (23) and Dicer (12, 16). To date more than 4000 microRNAs have been annotated in vertebrates, invertebrates and plants according to the miRBase database release 9.0 in October 2006 (10), and many miRNAs that correspond to putative genes have also been identified. Some miRNAs have multiple loci in the genome (32) and occasionally, several miRNA genes are arranged in tandem clusters (20). Recent bioinformatic predictions combined with array analyses, small RNA cloning and Northern blot validation indicate that the total number of miRNAs in vertebrate genomes is significantly higher than previously estimated and maybe as many as 1000 (2, 3, 36).
The first miRNAs genes to be discovered, lin-4 and let-7, base-pair incompletely to repeated elements in the 3’ untranslated regions (UTRs) of other heterochronic genes, and control developmental timing in the roundworm C. elegans by regulating translation directly and negatively via antisense RNA–RNA interaction (22, 31). The majority of plant miRNAs have perfect or near-perfect complementarity with their target sites and direct RISC-mediated target mRNA cleavage, whereas most animal miRNAs recognize their target sites located in 3’-UTRs by incomplete base-pairing, resulting in translational repression of the target genes (1). |
miRNA function in animals An increasing body of research shows that animal miRNAs play fundamental biological roles in cell growth and apoptosis (4), hematopoietic lineage differentiation (6), homeobox gene regulation (37), neuronal asymmetry (14), insulin secretion (30), brain morphogenesis (9), cardiogenesis (38) and late embryonic development in vertebrates (7, 35). Several studies have identified subclasses of miRNAs directly implicated in the regulation of mammalian brain development and neuronal differentiation (19, 27, 33, 34). Interestingly, many neural miRNAs appear to be temporally regulated in cortical cultures copurifying with polyribosomes, suggesting that they may control localized translation of dendrite-specific mRNAs (17). The number of regulatory mRNA targets of vertebrate miRNAs was recently estimated by identifying conserved complementarity to the seed sequence of the miRNAs, suggesting that ~30 % of the human genes may be controlled by miRNAs, with an average of ~200 mRNA targets per miRNA (18, 24). |
miRNAs in human disease The expanding inventory of human miRNAs along with their highly diverse expression patterns and high number of potential target mRNAs suggest that miRNAs are involved in a wide variety of human diseases. One is spinal muscular atrophy, a paediatric neurodegenerative disease caused by reduced protein levels or loss-of-function mutations of the survival of motor neurons gene (29). Other diseases in which miRNAs or their processing machinery have been implicated, include fragile X mental retardation caused by absence of the fragile X mental retardation protein (28) and DiGeorge syndrome (21). In addition, perturbed miRNA expression patterns have been reported in many human cancers. For example, the human miRNA genes miR15a and miR16-1 are deleted or down-regulated in the majority of B-cell chronic lymphocytic leukemia cases, while more than 50 % of the human miRNA genes are located in cancer-associated genomic regions or at fragile sites (5). Recently, systematic expression analysis of a diversity of human cancers revealed a general down-regulation of miRNAs in tumors compared to normal tissues (25). Interestingly, miRNA-based classification of poorly differentiated tumors was successful, whereas mRNA profiles were highly inaccurate when applied to the same samples. miRNAs have also been reported to be deregulated in breast cancer (13), lung cancer (15) and colon cancer (26), while the miR-17-92 cluster, which is amplified in human B-cell lymphomas and miR-155 which is upregulated in Burkitt’s lymphoma have been reported as the first human miRNA oncogenes (8, 11). |
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| References
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