MicroRNAs in Human Health and Disease

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The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid. The irreversible flow of information is from DNA to RNA to protein; DNA is transcribed into messenger RNA (mRNA) and subsequently translated into protein. However, in recent years it has become clear that additional genetic information exists in the human genome. Non-protein coding RNA (ncRNA) refers to mRNA that is transcribed from DNA but is not translated into protein. These sequences, once thought of as “junk DNA” – portions of the DNA sequence of the genome that don’t have a function – are being found to have crucial roles in human development, physiology and disease. Indeed, recent studies suggest that there are thousands of ncRNAs in the human genome [1-2].

Non-coding RNAs include a class of molecules called microRNAs (miRNAs or miRs). MicroRNAs are highly expressed in normal tissues and are being found to have critical roles in gene regulatory processes during cellular development and differentiation. MicroRNAs are small ncRNAs ~21-nucleotides long that regulate gene expression at the post-transcriptional level. MicroRNAs function by binding target mRNA molecules and either inhibiting translation into protein or targeting them for degradation. Abnormal microRNA expression has been linked to many human diseases, including schizophrenia, autism and cancer.

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MicroRNAs (miRNAs) are transcribed from DNA to produce a stem-loop structure containing a primary transcript called a pri-miRNA that ranges in size from hundreds of nucleotides to tens of kilobases. In the nucleus, pri-miRNAs are processed to shorter ~70 nucleotide hairpin precursor miRNAs known as pre-miRNAs by a multiprotein complex called the Microprocessor complex, which consist of the core components Drosha, an RNase III enzyme, and Pasah, a double-stranded RNA binding protein. The pre-miRNA is transported to the cytoplasm and processed by another RNase III enzyme, Dicer, to produce mature ~22-nucleotide miRNA:miRNA duplexes. A ribonucleoprotein complex called miRSC is then assembled with one strand of the miRNA duplex called the guide strand (purple in figure). Depending upon partial or exact complementarity to messenger RNA, miRISC mediates inhibition of translation or messenger RNA degradation [3].

MicroRNAs represent exciting cutting-edge biomarkers for present and future clinical use that are actively being investigated. Currently, there are three commercially available molecular diagnostic tests for cancer based on microRNAs, all from Rosetta Genomics. In addition, microRNAs have potential application as prognostic indicators and therapeutic targets.

For more information on microRNAs, see:

• miRNA Blog
• You’d Prefer An Argonaute

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References

1. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. ENCODE Project Consortium. Nature. 2007 Jun 14;447(7146):799-816.
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2. Washietl et al. Structured RNAs in the ENCODE selected regions of the human genome. Genome Res. 2007 Jun;17(6):852-64.
   View abstract
3. Filipowicz et al. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 2008 Feb;9(2):102-14.
   View abstract