Relative Contribution of Sequence and Structure Features to the MRNA Binding of Argonaute/EIF2C-miRNA Complexes and the Degradation of MiRNA Targets

Overview

Journal Genome Res

Specialty Genetics

Date 2009 Sep 22

PMID 19767416

Citations 56

Authors

Jean Hausser

Markus Landthaler

Lukasz Jaskiewicz

Dimos Gaidatzis

Mihaela Zavolan

Affiliations

Soon will be listed here.

Abstract

How miRNAs recognize their target sites is a puzzle that many experimental and computational studies aimed to solve. Several features, such as perfect pairing of the miRNA seed, additional pairing in the 3' region of the miRNA, relative position in the 3' UTR, and the A/U content of the environment of the putative site, have been found to be relevant. Here we have used a large number of previously published data sets to assess the power that various sequence and structure features have in distinguishing between putative sites that do and those that do not appear to be functional. We found that although different data sets give widely different answers when it comes to ranking the relative importance of these features, the sites inferred from most transcriptomics experiments, as well as from comparative genomics, appear similar at this level. This suggests that miRNA target sites have been selected in evolution on their ability to trigger mRNA degradation. To understand at what step in the miRNA-induced response individual features play a role, we transfected human HEK293 cells with miRNAs and analyzed the association of Argonaute/EIF2C-miRNA complexes with target mRNAs and the degradation of these messages. We found that structural features of the target site are only important for Argonaute/EIF2C binding, while sequence features such as the A/U content of the 3' UTR are important for mRNA degradation.

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References

Grimson A, Farh K, Johnston W, Garrett-Engele P, Lim L, Bartel D . MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007; 27(1):91-105. PMC: 3800283. DOI: 10.1016/j.molcel.2007.06.017. View

Krutzfeldt J, Rajewsky N, Braich R, Rajeev K, Tuschl T, Manoharan M . Silencing of microRNAs in vivo with 'antagomirs'. Nature. 2005; 438(7068):685-9. DOI: 10.1038/nature04303. View

Landthaler M, Gaidatzis D, Rothballer A, Chen P, Soll S, Dinic L . Molecular characterization of human Argonaute-containing ribonucleoprotein complexes and their bound target mRNAs. RNA. 2008; 14(12):2580-96. PMC: 2590962. DOI: 10.1261/rna.1351608. View

Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N . Widespread changes in protein synthesis induced by microRNAs. Nature. 2008; 455(7209):58-63. DOI: 10.1038/nature07228. View

Lewis B, Burge C, Bartel D . Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005; 120(1):15-20. DOI: 10.1016/j.cell.2004.12.035. View

Majoros W, Ohler U . Spatial preferences of microRNA targets in 3' untranslated regions. BMC Genomics. 2007; 8:152. PMC: 1904200. DOI: 10.1186/1471-2164-8-152. View

Stark A, Brennecke J, Bushati N, Russell R, Cohen S . Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution. Cell. 2005; 123(6):1133-46. DOI: 10.1016/j.cell.2005.11.023. View

Long D, Lee R, Williams P, Chan C, Ambros V, Ding Y . Potent effect of target structure on microRNA function. Nat Struct Mol Biol. 2007; 14(4):287-94. DOI: 10.1038/nsmb1226. View

Hammell M, Long D, Zhang L, Lee A, Carmack C, Han M . mirWIP: microRNA target prediction based on microRNA-containing ribonucleoprotein-enriched transcripts. Nat Methods. 2009; 5(9):813-9. PMC: 3092588. DOI: 10.1038/nmeth.1247. View

10.

Lim L, Lau N, Garrett-Engele P, Grimson A, Schelter J, Castle J . Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005; 433(7027):769-73. DOI: 10.1038/nature03315. View

11.

Karginov F, Conaco C, Xuan Z, Schmidt B, Parker J, Mandel G . A biochemical approach to identifying microRNA targets. Proc Natl Acad Sci U S A. 2007; 104(49):19291-6. PMC: 2148283. DOI: 10.1073/pnas.0709971104. View

12.

Kedde M, Strasser M, Boldajipour B, Vrielink J, Slanchev K, le Sage C . RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell. 2007; 131(7):1273-86. DOI: 10.1016/j.cell.2007.11.034. View

13.

Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T . Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell. 2004; 15(2):185-97. DOI: 10.1016/j.molcel.2004.07.007. View

14.

Reinhart B, Slack F, Basson M, Pasquinelli A, Bettinger J, Rougvie A . The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000; 403(6772):901-6. DOI: 10.1038/35002607. View

15.

Zhao Y, Ransom J, Li A, Vedantham V, von Drehle M, Muth A . Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007; 129(2):303-17. DOI: 10.1016/j.cell.2007.03.030. View

16.

Robins H, Press W . Human microRNAs target a functionally distinct population of genes with AT-rich 3' UTRs. Proc Natl Acad Sci U S A. 2005; 102(43):15557-62. PMC: 1257391. DOI: 10.1073/pnas.0507443102. View

17.

Linsley P, Schelter J, Burchard J, Kibukawa M, Martin M, Bartz S . Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Mol Cell Biol. 2007; 27(6):2240-52. PMC: 1820501. DOI: 10.1128/MCB.02005-06. View

18.

Khan A, Betel D, Miller M, Sander C, Leslie C, Marks D . Transfection of small RNAs globally perturbs gene regulation by endogenous microRNAs. Nat Biotechnol. 2009; 27(6):549-55. PMC: 2782465. DOI: 10.1038/nbt.1543. View

19.

Kertesz M, Iovino N, Unnerstall U, Gaul U, Segal E . The role of site accessibility in microRNA target recognition. Nat Genet. 2007; 39(10):1278-84. DOI: 10.1038/ng2135. View

20.

Robins H, Li Y, Padgett R . Incorporating structure to predict microRNA targets. Proc Natl Acad Sci U S A. 2005; 102(11):4006-9. PMC: 554828. DOI: 10.1073/pnas.0500775102. View