The roles of binding site arrangement and combinatorial targeting in microRNA repression of gene expression.
BACKGROUND
MicroRNAs (miRNAs) are small noncoding RNAs that bind mRNA target transcripts and repress gene expression. They have been implicated in multiple diseases, such as cancer, but the mechanisms of this involvement are not well understood. Given the complexity and degree of interactions between miRNAs and target genes, understanding how miRNAs achieve their specificity is important to understanding miRNA function and identifying their role in disease.


RESULTS
Here we report factors that influence miRNA regulation by considering the effects of both single and multiple miRNAs targeting human genes. In the case of single miRNA targeting, we developed a metric that integrates miRNA and mRNA expression data to calculate how changes in miRNA expression affect target mRNA expression. Using the metric, our global analysis shows that the repression of a given miRNA on a target mRNA is modulated by 3' untranslated region length, the number of target sites, and the distance between a pair of binding sites. Additionally, we show that some miRNAs preferentially repress transcripts with longer CTG repeats, suggesting a possible role for miRNAs in repeat expansion disorders such as myotonic dystrophy. We also examine the large class of genes targeted by multiple miRNAs and show that specific types of genes are progressively more enriched as the number of targeting miRNAs increases. Expression microarray data further show that these highly targeted genes are downregulated relative to genes targeted by few miRNAs, which suggests that highly targeted genes are tightly regulated and that their dysregulation may lead to disease. In support of this idea, cancer genes are strongly enriched among highly targeted genes.


CONCLUSIONS
Our data show that the rules governing miRNA targeting are complex, but that understanding the mechanisms that drive such control can uncover miRNAs' role in disease. Our study suggests that the number and arrangement of miRNA recognition sites can influence the degree and specificity of miRNA-mediated gene repression.
Hon
Lawrence S
LS
Department of Bioinformatics, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080, USA. lhon@gene.com
Zhang
Zemin
Z
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004285:Dogs; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D051381:Rats
D035683:MicroRNAs
Cell. 2005 Jan 14;120(1):21-4
15652478
Nucleic Acids Res. 2007;35(7):2333-42
17389647
Nature. 2005 Feb 17;433(7027):769-73
15685193
Nat Genet. 2000 May;25(1):25-9
10802651
Nature. 2001 Jan 18;409(6818):363-6
11201747
Science. 2001 Aug 10;293(5532):1146-50
11498593
Hum Mol Genet. 2001 Sep 15;10(19):2165-70
11590133
Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15149-54
11742071
Genes Dev. 2003 Feb 15;17(4):438-42
12600936
J Cell Sci. 2007 Jun 1;120(Pt 11):1833-40
17515481
Genome Biol. 2003;4(5):P3
12734009
Trends Genet. 2003 Jul;19(7):362-5
12850439
Nature. 2003 Sep 25;425(6956):415-9
14508493
Genome Res. 2003 Dec;13(12):2602-8
14613975
Genes Dev. 2003 Dec 15;17(24):3011-6
14681208
Science. 2004 Jan 2;303(5654):95-8
14631048
Genome Biol. 2003;5(1):R1
14709173
Genes Dev. 2004 Jan 15;18(2):132-7
14729570
Hum Mol Genet. 2004 Mar 1;13(5):495-507
14722159
Nat Rev Cancer. 2004 Mar;4(3):177-83
14993899
Genes Dev. 2004 Mar 1;18(5):504-11
15014042
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7
15075390
RNA. 2004 Oct;10(10):1518-25
15337849
RNA. 2004 Nov;10(11):1813-9
15496526
J Cell Biol. 1995 Mar;128(6):995-1002
7896884
PLoS Biol. 2004 Nov;2(11):e363
15502875
Cell. 2005 Jan 14;120(1):15-20
15652477
PLoS Biol. 2005 Mar;3(3):e85
15723116
Nat Genet. 2005 May;37(5):495-500
15806104
Nature. 2005 Jun 9;435(7043):828-33
15944707
Nature. 2005 Jun 9;435(7043):834-8
15944708
J Cell Sci. 2005 Jul 1;118(Pt 13):2923-33
15961406
Nat Rev Genet. 2005 Oct;6(10):743-55
16205714
FEBS Lett. 2005 Oct 31;579(26):5911-22
16111679
FEBS Lett. 2005 Oct 31;579(26):5923-31
16144699
Nature. 2005 Dec 1;438(7068):685-9
16258535
Science. 2005 Dec 16;310(5755):1817-21
16308420
Cell. 2005 Dec 16;123(6):1133-46
16337999
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D140-4
16381832
Trends Genet. 2006 Mar;22(3):165-73
16446010
Curr Biol. 2006 Mar 7;16(5):460-71
16458514
Mol Cancer Ther. 2007 May;6(5):1483-91
17483436
Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4034-9
16495412
Nat Rev Cancer. 2006 Apr;6(4):259-69
16557279
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2746-51
16477010
Nat Genet. 2006 Jun;38 Suppl:S20-4
16736020
PLoS Comput Biol. 2005 Dec;1(7):e69
16355253
Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9136-41
16754881
Annu Rev Neurosci. 2006;29:259-77
16776586
Nat Genet. 2006 Jul;38(7):813-8
16751773
Genes Dev. 2006 Jul 15;20(14):1885-98
16815998
Nat Struct Mol Biol. 2006 Sep;13(9):849-51
16921378
Cell. 2006 Sep 22;126(6):1203-17
16990141
Genes Dev. 2006 Oct 15;20(20):2769-72
17043305
Nucleic Acids Res. 2006;34(17):4801-15
16971455
Sci STKE. 2007 Jan 2;2007(367):re1
17200520
Nucleic Acids Res. 2007 Jan;35(Database issue):D61-5
17130148
Science. 2007 Jan 5;315(5808):97-100
17204650
Nucleic Acids Res. 2007;35(1):152-64
17158157
Biochim Biophys Acta. 2007 Feb;1772(2):195-204
16876389
Mol Cell. 2007 Feb 23;25(4):575-86
17317629
Nat Struct Mol Biol. 2005 Feb;12(2):133-7
15643423