Nature Reviews Genetics 5; 631(2004); doi:10.1038/nrg1415

MicroRNAs: small RNAs with a big role in gene regulation

Nature Reviews Genetics 5; 631(2004); doi:10.1038/nrg1415MicroRNAs: small RNAs with a big role in gene regulation

Figure 2 | The current model for the biogenesis and post-transcriptional suppression of microRNAs and small interfering RNAs.

microRNAs1. Derived from an endogenous, structured transcript (pre-miRNA)2. One miRNA accumulates3. Evolutionary conserved4. Usually located away from genes5. Imperfect pairing blocks translation6. Incorporated into miRNP7. Regulate expression of genes encoded at another locus8. miRNAs bind to the target 3' UTRs through imperfect complementarity at multiple sites

siRNAs1. Derived from extended dsRNA2. Each dsRNA gives multiple siRNAs3. Less conservation4. Nearly complementary to target RNA (self-targeting)5. Perfect pairing induces target RNA cleavage6. Incorporated into RISC7. Regulate the locus from which their sequence derives8. siRNAs often form a perfect duplex with their targets at only one site.

miRNAs and siRNAs — what's the difference?miRNAs and siRNAs — what's the difference?

Figure 1 |  The molecular hallmarks of lin-4, the founding member of the microRNA family. 

Fig. 1: C. elegans worms that contain mutations in the let-7 miRNA gene develop abnormally, often rupturing at the midsection. The let-7 miRNA is expressed in most animals, including humans, where it may also play an essential role in regulating development.

Fig. 1. Correlation between FRAs and miRs. A karyotype showing the position of 113 FRAs and 186 miRs is presented. The 61 miRs located in the same chromosomal band as the FRA are red. We were able to precisely locate 35 miRs inside 12 cloned FRAs. The red arrow shows frequently observed FRAs

Human microRNA genes are frequently located atfragile sites and genomic regions involved in cancersGeorge Adrian Calin*†, Cinzia Sevignani*†, Calin Dan Dumitru*, Terry Hyslop‡, Evan Noch*, Sai Yendamuri*,Masayoshi Shimizu*, Sashi Rattan*, Florencia Bullrich*, Massimo Negrini*§, and Carlo M. Croce*¶

PNAS2004

Fig. 3. MiRs as cancer players. Some of these proposed mechanisms areexperimentally proven, like the HD of miR-15amiR-16a cluster in B-CLL (9),the c-myc overexpression by the reposition near a putative miR promoter, ormiR143miR-145 cluster down-regulation in colon cancers (39).

Human microRNA genes are frequently located atfragile sites and genomic regions involved in cancersGeorge Adrian Calin*†, Cinzia Sevignani*†, Calin Dan Dumitru*, Terry Hyslop‡, Evan Noch*, Sai Yendamuri*,Masayoshi Shimizu*, Sashi Rattan*, Florencia Bullrich*, Massimo Negrini*§, and Carlo M. Croce*¶

PNAS2004

Possible correlations between the genomic position of a large number of miRs and the location of cancer-associated genomic regions???

Table 2. Examples of miRs located in minimal deleted regions, minimal amplified regions, and breakpoint regions involved inhuman cancers

Evolutionary Conservation of miRNAs• miRNAs are evolutionary conserved even across phyla• This suggests ancient and important roles for this class of regulators• Observation: Found in multicellular plants and animals but not inunicellular eukaryotes• Question: How many of these tiny regulators are hidden in animalgenomes?

Correlations between miRNAs and DiseaseCalin et al. (2002) Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in

chronic lymphocytic leukemia. Proc. Nat. Aca. Sci. 99, 15524-9. Caudy AA, Myers M, Hannon GJ, Hammond SM. (2002) Fragile X-related protein and VIG associate with the

RNA interference machinery. Genes Dev. 16, 2491-6.Chapman EJ, Prokhnevsky AI, Gopinath K, Dolja VV, Carrington JC. (2004) “ Viral RNA silencing suppressors

inhibit the microRNA pathway at an intermediate step,” Genes Dev. 18(10):1179-86. [Abstract] Chen J, Li WX, Xie D, Peng JR, Ding SW. (2004) “ Viral Virulence Protein Suppresses RNA Silencing-

Mediated Defense but Upregulates the Role of MicroRNA in Host Gene Expression,” Plant Cell. 16(5):1302-13. [Abstract]

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, 631-2.

Jin P, Zarnescu DC, Ceman S, Nakamoto M, Mowrey J, Jongens TA, Nelson DL, Moses K, Warren ST. (2003) “ Biochemical and genetic interaction between the fragile X mental retardation protein and the

microRNA pathway,” Nat Neurosci. 7(2):113-7 [Abstract] McManus MT. (2003) “ MicroRNAs and cancer,” Semin Cancer Biol. 13(4):253-8. [Abstract]

Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A. (2003) “ High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma,” Genes Chromosomes Cancer. 39(2):167-9. [Abstract]

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.

Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T. Reduced expression of the let-7 microRNAs in human lung cancers in

association with shortened postoperative survival. Cancer Res. 2004 Jun 1;64(11):3753-6. [Abstract]