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Nature Reviews Genetics 5; 631(2004); doi:10.1038/nrg1415
MicroRNAs: 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.
Nature Reviews Genetics 5; 631(2004); doi:10.1038/nrg1415
MicroRNAs: small RNAs with a big role in gene regulation
miRNAs and siRNAs — what's the difference?
microRNAs
1. Derived from an endogenous, structured
transcript (pre-miRNA)
2. One miRNA accumulates
3. Evolutionary conserved
4. Usually located away from genes
5. Imperfect pairing blocks translation
6. Incorporated into miRNP
7. Regulate expression of genes encoded at
another locus
8. miRNAs bind to the target 3' UTRs through
imperfect complementarity at multiple sites
siRNAs
1. Derived from extended dsRNA
2. Each dsRNA gives multiple siRNAs
3. Less conservation
4. Nearly complementary to target RNA
(self-targeting)
5. Perfect pairing induces target RNA
cleavage
6. Incorporated into RISC
7. Regulate the locus from which their
sequence derives
8. siRNAs often form a perfect duplex with
their targets at only one site.
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.
Human microRNA genes are frequently located at
fragile sites and genomic regions involved in cancers
George 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. 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 at
fragile sites and genomic regions involved in cancers
George 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???
Fig. 3. MiRs as cancer players. Some of these proposed mechanisms are
experimentally 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, or
miR143miR-145 cluster down-regulation in colon cancers (39).
Table 2. Examples of miRs located in minimal deleted regions, minimal
amplified regions, and breakpoint regions involved in
human 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 in
unicellular eukaryotes
• Question: How many of these tiny regulators are hidden in animal
genomes?
Correlations between miRNAs and Disease
Calin 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 SilencingMediated 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 microRNA155/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]