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PMID: 17612493 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

MicroRNA targeting specificity in mammals: determinants beyond seed pairing.

Molecular cell ·Vol. 27 ·No. 1 ·2007-07-06 ·Pages 91-105

Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP

Abstract

Mammalian microRNAs (miRNAs) pair to 3'UTRs of mRNAs to direct their posttranscriptional repression. Important for target recognition are approximately 7 nt sites that match the seed region of the miRNA. However, these seed matches are not always sufficient for repression, indicating that other characteristics help specify targeting. By combining computational and experimental approaches, we uncovered five general features of site context that boost site efficacy: AU-rich nucleotide composition near the site, proximity to sites for coexpressed miRNAs (which leads to cooperative action), proximity to residues pairing to miRNA nucleotides 13-16, positioning within the 3'UTR at least 15 nt from the stop codon, and positioning away from the center of long UTRs. A model combining these context determinants quantitatively predicts site performance both for exogenously added miRNAs and for endogenous miRNA-message interactions. Because it predicts site efficacy without recourse to evolutionary conservation, the model also identifies effective nonconserved sites and siRNA off-targets.

MeSH Terms
3' Untranslated Regions/genetics Animals Base Pairing/genetics Base Sequence Binding Sites Codon, Terminator/genetics Conserved Sequence Down-Regulation/genetics HeLa Cells Humans Mammals/genetics MicroRNAs/chemistry,genetics,metabolism Models, Genetic Molecular Sequence Data Nucleotides/genetics RNA, Messenger/genetics,metabolism Substrate Specificity
Chemicals
3' Untranslated Regions Codon, Terminator MicroRNAs Nucleotides RNA, Messenger
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Grimson Andrew
Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Farh Kyle Kai-How
Johnston Wendy K
Garrett-Engele Philip
Lim Lee P
Bartel David P
References (32)
32 references, click to expand
  1. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans.
    Nature. 2000 Feb 24;403(6772):901-6 PMID: 10706289
  2. Requirement of bic/microRNA-155 for normal immune function.
    Science. 2007 Apr 27;316(5824):608-11 PMID: 17463290
  3. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans.
    Science. 2001 Oct 26;294(5543):858-62 PMID: 11679671
  4. A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans.
    Nature. 2003 Dec 18;426(6968):845-9 PMID: 14685240
  5. Prediction of mammalian microRNA targets.
    Cell. 2003 Dec 26;115(7):787-98 PMID: 14697198
  6. MicroRNAs: genomics, biogenesis, mechanism, and function.
    Cell. 2004 Jan 23;116(2):281-97 PMID: 14744438
  7. Specificity of microRNA target selection in translational repression.
    Genes Dev. 2004 Mar 1;18(5):504-11 PMID: 15014042
  8. Aligning multiple genomic sequences with the threaded blockset aligner.
    Genome Res. 2004 Apr;14(4):708-15 PMID: 15060014
  9. MicroRNA-directed cleavage of HOXB8 mRNA.
    Science. 2004 Apr 23;304(5670):594-6 PMID: 15105502
  10. Fast and effective prediction of microRNA/target duplexes.
    RNA. 2004 Oct;10(10):1507-17 PMID: 15383676
  11. Distance constraints between microRNA target sites dictate efficacy and cooperativity.
    Nucleic Acids Res. 2007;35(7):2333-42 PMID: 17389647
  12. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.
    Cell. 1993 Dec 3;75(5):843-54 PMID: 8252621
  13. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans.
    Cell. 1993 Dec 3;75(5):855-62 PMID: 8252622
  14. Expanded sequence dependence of thermodynamic parameters improves prediction of RNA secondary structure.
    J Mol Biol. 1999 May 21;288(5):911-40 PMID: 10329189
  15. Human MicroRNA targets.
    PLoS Biol. 2004 Nov;2(11):e363 PMID: 15502875
  16. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.
    Cell. 2005 Jan 14;120(1):15-20 PMID: 15652477
  17. mRNA helicase activity of the ribosome.
    Cell. 2005 Jan 14;120(1):49-58 PMID: 15652481
  18. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs.
    Nature. 2005 Feb 17;433(7027):769-73 PMID: 15685193
  19. Incorporating structure to predict microRNA targets.
    Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4006-9 PMID: 15738385
  20. Principles of microRNA-target recognition.
    PLoS Biol. 2005 Mar;3(3):e85 PMID: 15723116
  21. Combinatorial microRNA target predictions.
    Nat Genet. 2005 May;37(5):495-500 PMID: 15806104
  22. Pervasive regulation of Drosophila Notch target genes by GY-box-, Brd-box-, and K-box-class microRNAs.
    Genes Dev. 2005 May 1;19(9):1067-80 PMID: 15833912
  23. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis.
    Nature. 2005 Jul 14;436(7048):214-20 PMID: 15951802
  24. Human microRNAs target a functionally distinct population of genes with AT-rich 3' UTRs.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15557-62 PMID: 16230613
  25. Silencing of microRNAs in vivo with 'antagomirs'.
    Nature. 2005 Dec 1;438(7068):685-9 PMID: 16258535
  26. Compact and ordered collapse of randomly generated RNA sequences.
    Nat Struct Mol Biol. 2005 Dec;12(12):1130-6 PMID: 16273104
  27. The widespread impact of mammalian MicroRNAs on mRNA repression and evolution.
    Science. 2005 Dec 16;310(5755):1817-21 PMID: 16308420
  28. Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs.
    Science. 2006 Apr 7;312(5770):75-9 PMID: 16484454
  29. A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes.
    Cell. 2006 Sep 22;126(6):1203-17 PMID: 16990141
  30. Potent effect of target structure on microRNA function.
    Nat Struct Mol Biol. 2007 Apr;14(4):287-94 PMID: 17401373
  31. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2.
    Cell. 2007 Apr 20;129(2):303-17 PMID: 17397913
  32. The path of messenger RNA through the ribosome.
    Cell. 2001 Jul 27;106(2):233-41 PMID: 11511350
Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-2765
DOI
10.1016/j.molcel.2007.06.017
Published
2007-07-06
Pages
91-105
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3800283
Subset
IM
Grants
NIGMS NIH HHS · R01 GM067031 · United States
External Links
PubMed source DOI: 10.1016/j.molcel.2007.06.017 PMC Full Text View journal details
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