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MicroRNA Target Recognition: Insights from Transcriptome-Wide Non-Canonical Interactions
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  • Journal title : Molecules and Cells
  • Volume 39, Issue 5,  2016, pp.375-381
  • Publisher : Korea Society for Molecular and Cellular Biology
  • DOI : 10.14348/molcells.2016.0013
 Title & Authors
MicroRNA Target Recognition: Insights from Transcriptome-Wide Non-Canonical Interactions
Seok, Heeyoung; Ham, Juyoung; Jang, Eun-Sook; Chi, Sung Wook;
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MicroRNAs (miRNAs) are small non-coding RNAs (~22 nucleotides) regulating gene expression at the post-transcriptional level. By directing the RNA-induced silencing complex (RISC) to bind specific target mRNAs, miRNA can repress target genes and affect various biological phenotypes. Functional miRNA target recognition is known to majorly attribute specificity to consecutive pairing with seed region (position 2-8) of miRNA. Recent advances in a transcriptome-wide method of mapping miRNA binding sites (Ago HITS-CLIP) elucidated that a large portion of miRNA-target interactions in vivo are mediated not only through the canonical "seed sites" but also via non-canonical sites (~15-80%), setting the stage to expand and determine their properties. Here we focus on recent findings from transcriptome-wide non-canonical miRNA-target interactions, specifically regarding "nucleation bulges" and "seed-like motifs". We also discuss insights from Ago HITS-CLIP data alongside structural and biochemical studies, which highlight putative mechanisms of miRNA target recognition, and the biological significance of these non-canonical sites mediating marginal repression.
argonaute;CLIP;microRNA;non-canonical targets;
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Agarwal, V., Bell, G.W., Nam, J.W., and Bartel, D.P. (2015). Predicting effective microRNA target sites in mammalian mRNAs. eLife 4.

Ambros, V. (2004). The functions of animal microRNAs. Nature 431, 350-355. crossref(new window)

Baek, D., Villen, J., Shin, C., Camargo, F.D., Gygi, S.P., and Bartel, D.P. (2008). The impact of microRNAs on protein output. Nature 455, 64-71. crossref(new window)

Bartel, D.P. (2009). MicroRNAs: target recognition and regulatory functions. Cell 136, 215-233. crossref(new window)

Bernstein, E., Kim, S.Y., Carmell, M.A., Murchison, E.P., Alcorn, H., Li, M.Z., Mills, A.A., Elledge, S.J., Anderson, K.V., and Hannon, G.J. (2003). Dicer is essential for mouse development. Nat. Genet. 35, 215-217. crossref(new window)

Boudreau, R.L., Jiang, P., Gilmore, B.L., Spengler, R.M., Tirabassi, R., Nelson, J.A., Ross, C.A., Xing, Y., and Davidson, B.L. (2014). Transcriptome-wide discovery of microRNA binding sites in human brain. Neuron 81, 294-305. crossref(new window)

Brennecke, J., Stark, A., Russell, R.B., and Cohen, S.M. (2005). Principles of microRNA-target recognition. PLoS Biol. 3, e85. crossref(new window)

Brodersen, P., and Voinnet, O. (2009). Revisiting the principles of microRNA target recognition and mode of action. Nat. Rev. Mol. Cell Biol. 10, 141-148.

Chandradoss, S.D., Schirle, N.T., Szczepaniak, M., MacRae, I.J., and Joo, C. (2015). A dynamic search process underlies microRNA targeting. Cell 162, 96-107. crossref(new window)

Chi, S.W., Zang, J.B., Mele, A., and Darnell, R.B. (2009). Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 460, 479-486. crossref(new window)

Chi, S.W., Hannon, G.J., and Darnell, R.B. (2012). An alternative mode of microRNA target recognition. Nat. Struct. Mol. Biol. 19, 321-327. crossref(new window)

Croce, C.M. (2009). Causes and consequences of microRNA dysregulation in cancer. Nat. Rev. Genet. 10, 704-714. crossref(new window)

Didiano, D., and Hobert, O. (2006). Perfect seed pairing is not a generally reliable predictor for miRNA-target interactions. Nat. Struct Mol. Biol. 13, 849-851. crossref(new window)

Easow, G., Teleman, A.A., and Cohen, S.M. (2007). Isolation of microRNA targets by miRNP immunopurification. RNA 13, 1198-1204. crossref(new window)

Eichhorn, S.W., Guo, H., McGeary, S.E., Rodriguez-Mias, R.A., Shin, C., Baek, D., Hsu, S.H., Ghoshal, K., Villen, J., and Bartel, D.P. (2014). mRNA destabilization is the dominant effect of mammalian microRNAs by the time substantial repression ensues. Mol. Cell 56, 104-115. crossref(new window)

Elkayam, E., Kuhn, C.D., Tocilj, A., Haase, A.D., Greene, E.M., Hannon, G.J., and Joshua-Tor, L. (2012). The structure of human argonaute-2 in complex with miR-20a. Cell 150, 100-110. crossref(new window)

Fabian, M.R., Sonenberg, N., and Filipowicz, W. (2010). Regulation of mRNA translation and stability by microRNAs. Ann. Rev. Biochem. 79, 351-379. crossref(new window)

Filipowicz, W. (2005). RNAi: the nuts and bolts of the RISC machine. Cell 122, 17-20. crossref(new window)

Friedman, R.C., Farh, K.K., Burge, C.B., and Bartel, D.P. (2009). Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92-105.

Grimson, A. (2007). MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol. Cell 27, 91-105. crossref(new window)

Grosswendt, S., Filipchyk, A., Manzano, M., Klironomos, F., Schilling, M., Herzog, M., Gottwein, E., and Rajewsky, N. (2014). Unambiguous identification of miRNA:target site interactions by different types of ligation reactions. Mol. Cell 54, 1042-1054. crossref(new window)

Guo, H., Ingolia, N.T., Weissman, J.S., and Bartel, D.P. (2010). Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466, 835-840. crossref(new window)

Haecker, I., Gay, L.A., Yang, Y., Hu, J., Morse, A.M., McIntyre, L.M., and Renne, R. (2012). Ago HITS-CLIP expands understanding of Kaposi's sarcoma-associated herpesvirus miRNA function in primary effusion lymphomas. PLoS Pathog. 8, e1002884. crossref(new window)

Hafner, M., Landthaler, M., Burger, L., Khorshid, M., Hausser, J., Berninger, P., Rothballer, A., Ascano, M., Jr., Jungkamp, A.C., Munschauer, M., et al. (2010). Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141, 129-141. crossref(new window)

Hammell, M. (2008). mirWIP: microRNA target prediction based on microRNA-containing ribonucleoprotein-enriched transcripts. Nat. Methods 5, 813-819. crossref(new window)

He, L., and Hannon, G.J. (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nat. Rev. Genet. 5, 522-531. crossref(new window)

Hebert, S.S., and De Strooper, B. (2009). Alterations of the microRNA network cause neurodegenerative disease. Trend Neurosci. 32, 199-206. crossref(new window)

Helwak, A., Kudla, G., Dudnakova, T., and Tollervey, D. (2013). Mapping the human miRNA interactome by CLASH reveals frequent noncanonical binding. Cell 153, 654-665. crossref(new window)

Hendrickson, D.G., Hogan, D.J., Herschlag, D., Ferrell, J.E., and Brown, P.O. (2008). Systematic identification of mRNAs recruited to argonaute 2 by specific microRNAs and corresponding changes in transcript abundance. PLoS One 3, e2126. crossref(new window)

Jo, M.H., Shin, S., Jung, S.R., Kim, E., Song, J.J., and Hohng, S. (2015). Human argonaute 2 has diverse reaction pathways on target RNAs. Mol. Cell 59, 117-124. crossref(new window)

John, B., Enright, A.J., Aravin, A., Tuschl, T., Sander, C., and Marks, D.S. (2004). Human MicroRNA targets. PLoS Biol. 2, e363. crossref(new window)

Kameswaran, V., Bramswig, N.C., McKenna, L.B., Penn, M., Schug, J., Hand, N.J., Chen, Y., Choi, I., Vourekas, A., Won, K.J., et al. (2014). Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets. Cell Metabol. 19, 135-145. crossref(new window)

Karginov, F.V. (2007). A biochemical approach to identifying microRNA targets. Proc. Natl. Acad. Sci. USA 104, 19291-19296. crossref(new window)

Kim, V.N. (2005). Small RNAs: classification, biogenesis, and function. Mol. Cells 19, 1-15. crossref(new window)

Kim, V.N., Han, J., and Siomi, M.C. (2009). Biogenesis of small RNAs in animals. Nat. Rev. Mol. Cell Biol. 10, 126-139.

Kim, K.K., Ham, J., and Chi, S.W. (2013). miRTCat: a comprehensive map of human and mouse microRNA target sites including non-canonical nucleation bulges. Bioinformatics 29, 1898-1899. crossref(new window)

Kim, S., Seo, D., Kim, D., Hong, Y., Chang, H., Baek, D., Kim, V.N., Lee, S., and Ahn, K. (2015). Temporal landscape of microRNAmediated host-virus crosstalk during productive human cytomegalovirus infection. Cell Host Microbe 17, 838-851. crossref(new window)

Kishore, S., Jaskiewicz, L., Burger, L., Hausser, J., Khorshid, M., and Zavolan, M. (2011). A quantitative analysis of CLIP methods for identifying binding sites of RNA-binding proteins. Nat. Methods 8, 559-564. crossref(new window)

Konig, J., Zarnack, K., Rot, G., Curk, T., Kayikci, M., Zupan, B., Turner, D.J., Luscombe, N.M., and Ule, J. (2010). iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat. Struct Mol. Biol. 17, 909-915. crossref(new window)

Kozomara, A., and Griffiths-Jones, S. (2014). miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 42, D68-73. crossref(new window)

Krek, A., Grun, D., Poy, M.N., Wolf, R., Rosenberg, L., Epstein, E.J., MacMenamin, P., da Piedade, I., Gunsalus, K.C., Stoffel, M., et al. (2005). Combinatorial microRNA target predictions. Nat. Genet. 37, 495-500. crossref(new window)

Lal, A., Navarro, F., Maher, C.A., Maliszewski, L.E., Yan, N., O'Day, E., Chowdhury, D., Dykxhoorn, D.M., Tsai, P., Hofmann, O., et al. (2009). miR-24 Inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to "seedless" 3'UTR microRNA recognition elements. Mol. Cell 35, 610-625. crossref(new window)

Lee, R.C., Feinbaum, R.L., and Ambros, V. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843-854. crossref(new window)

Lee, H.S., Seok, H., Lee, D.H., Ham, J., Lee, W., Youm, E.M., Yoo, J.S., Lee, Y.S., Jang, E.S., and Chi, S.W. (2015). Abasic pivot substitution harnesses target specificity of RNA interference. Nat. Commun. 6, 10154. crossref(new window)

Leung, A.K., Young, A.G., Bhutkar, A., Zheng, G.X., Bosson, A.D., Nielsen, C.B., and Sharp, P.A. (2011). Genome-wide identification of Ago2 binding sites from mouse embryonic stem cells with and without mature microRNAs. Nat. Struct Mol. Biol. 18, 237-244. crossref(new window)

Lewis, B.P., Shih, I.H., Jones-Rhoades, M.W., Bartel, D.P., and Burge, C.B. (2003). Prediction of mammalian microRNA targets. Cell 115, 787-798. crossref(new window)

Lewis, B.P., Burge, C.B., and Bartel, D.P. (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15-20. crossref(new window)

Licatalosi, D.D. (2008). HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456, 464-469. crossref(new window)

Lim, L.P. (2005). Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769-773. crossref(new window)

Liu, J., Carmell, M.A., Rivas, F.V., Marsden, C.G., Thomson, J.M., Song, J.J., Hammond, S.M., Joshua-Tor, L., and Hannon, G.J. (2004). Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437-1441. crossref(new window)

Loeb, G.B., Khan, A.A., Canner, D., Hiatt, J.B., Shendure, J., Darnell, R.B., Leslie, C.S., and Rudensky, A.Y. (2012). Transcriptome-wide miR-155 binding map reveals widespread noncanonical microRNA targeting. Mol. Cell 48, 760-770. crossref(new window)

Long, D., Lee, R., Williams, P., Chan, C.Y., Ambros, V., and Ding, Y. (2007). Potent effect of target structure on microRNA function. Nat. Struct Mol. Biol. 14, 287-294. crossref(new window)

Mili, S., and Steitz, J.A. (2004). Evidence for reassociation of RNAbinding proteins after cell lysis: implications for the interpretation of immunoprecipitation analyses. RNA 10, 1692-1694. crossref(new window)

Moore, M.J., Scheel, T.K., Luna, J.M., Park, C.Y., Fak, J.J., Nishiuchi, E., Rice, C.M., and Darnell, R.B. (2015). miRNA-target chimeras reveal miRNA 3'-end pairing as a major determinant of Argonaute target specificity. Nat. Commun. 6, 8864. crossref(new window)

Mourelatos, Z. (2008). Small RNAs: the seeds of silence. Nature 455, 44-45. crossref(new window)

Nakanishi, K., Weinberg, D.E., Bartel, D.P., and Patel, D.J. (2012). Structure of yeast Argonaute with guide RNA. Nature 486, 368-374. crossref(new window)

Olson, E.N. (2014). MicroRNAs as therapeutic targets and biomarkers of cardiovascular disease. Sci. Translational Med. 6, 239ps233.

Park, C.Y., Choi, Y.S., and McManus, M.T. (2010). Analysis of microRNA knockouts in mice. Hum. Mol. Genet. 19, R169-175. crossref(new window)

Poy, M.N., Eliasson, L., Krutzfeldt, J., Kuwajima, S., Ma, X., Macdonald, P.E., Pfeffer, S., Tuschl, T., Rajewsky, N., Rorsman, P., et al. (2004). A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226-230. crossref(new window)

Rajewsky, N. (2006). MicroRNA target predictions in animals. Nat. Genet. 38, S8-S13. crossref(new window)

Riley, K.J., Rabinowitz, G.S., Yario, T.A., Luna, J.M., Darnell, R.B., and Steitz, J.A. (2012a). EBV and human microRNAs co-target oncogenic and apoptotic viral and human genes during latency. EMBO J. 31, 2207-2221. crossref(new window)

Riley, K.J., Yario, T.A., and Steitz, J.A. (2012b). Association of Argonaute proteins and microRNAs can occur after cell lysis. RNA 18, 1581-1585. crossref(new window)

Salomon, W.E., Jolly, S.M., Moore, M.J., Zamore, P.D., and Serebrov, V. (2015). Single-molecule imaging reveals that argonaute reshapes the binding properties of its nucleic acid guides. Cell 162, 84-95. crossref(new window)

Schirle, N.T., and MacRae, I.J. (2012). The crystal structure of human Argonaute2. Science 336, 1037-1040. crossref(new window)

Schirle, N.T., Sheu-Gruttadauria, J., and MacRae, I.J. (2014). Structural basis for microRNA targeting. Science 346, 608-613. crossref(new window)

Selbach, M., Schwanhausser, B., Thierfelder, N., Fang, Z., Khanin, R., and Rajewsky, N. (2008). Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58-63. crossref(new window)

Seok, H., Jang, E.S., and Chi, S.W. (2016). Rationally designed siRNAs without miRNA-like off-target repression. BMB Rep. 49, 135-136. crossref(new window)

Shin, C., Nam, J.W., Farh, K.K., Chiang, H.R., Shkumatava, A., and Bartel, D.P. (2010). Expanding the microRNA targeting code: functional sites with centered pairing. Mol. Cell 38, 789-802. crossref(new window)

Sim, S.E., Bakes, J., and Kaang, B.K. (2014). Neuronal activitydependent regulation of microRNAs. Mol. Cells 37, 511-517. crossref(new window)

Stark, A., Brennecke, J., Russell, R.B., and Cohen, S.M. (2003). Identification of Drosophila microRNA targets. PLoS Biol. 1, E60. crossref(new window)

Stefani, G., and Slack, F.J. (2012). A 'pivotal' new rule for microRNA-mRNA interactions. Nat. Struct Mol. Biol. 19, 265-266. crossref(new window)

Tay, Y., Zhang, J., Thomson, A.M., Lim, B., and Rigoutsos, I. (2008). MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 455, 1124-1128. crossref(new window)

Tomari, Y., and Zamore, P.D. (2005). Perspective: machines for RNAi. Genes Dev. 19, 517-529. crossref(new window)

Ule, J. (2003). CLIP identifies Nova-regulated RNA networks in the brain. Science 302, 1212-1215. crossref(new window)

Vella, M.C., Choi, E.Y., Lin, S.Y., Reinert, K., and Slack, F.J. (2004). The C. elegans microRNA let-7 binds to imperfect let-7 complementary sites from the lin-41 3[prime]UTR. Genes Dev. 18, 132-137. crossref(new window)

Wang, Y., Juranek, S., Li, H., Sheng, G., Wardle, G.S., Tuschl, T., and Patel, D.J. (2009). Nucleation, propagation and cleavage of target RNAs in Ago silencing complexes. Nature 461, 754-761. crossref(new window)

Wee, L.M., Flores-Jasso, C.F., Salomon, W.E., and Zamore, P.D. (2012). Argonaute divides its RNA guide into domains with distinct functions and RNA-binding properties. Cell 151, 1055-1067. crossref(new window)

Wightman, B., Ha, I., and Ruvkun, G. (1993). Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75, 855-862. crossref(new window)

Xie, X., Lu, J., Kulbokas, E.J., Golub, T.R., Mootha, V., Lindblad-Toh, K., Lander, E.S., and Kellis, M. (2005). Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals. Nature 434, 338-345. crossref(new window)

Xue, Y., Ouyang, K., Huang, J., Zhou, Y., Ouyang, H., Li, H., Wang, G., Wu, Q., Wei, C., Bi, Y., et al. (2013). Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits. Cell 152, 82-96. crossref(new window)

Yao, C., Sasaki, H.M., Ueda, T., Tomari, Y., and Tadakuma, H. (2015). Single-molecule analysis of the target cleavage reaction by the Drosophila RNAi enzyme complex. Mol. Cell 59, 125-132. crossref(new window)

Yekta, S., Shih, I.H., and Bartel, D.P. (2004). MicroRNA-directed cleavage of HOXB8 mRNA. Science 304, 594-596. crossref(new window)

Zhang, C., and Darnell, R.B. (2011). Mapping in vivo protein-RNA interactions at single-nucleotide resolution from HITS-CLIP data. Nat. Biotechnol. 29, 607-614. crossref(new window)

Zisoulis, D.G., Lovci, M.T., Wilbert, M.L., Hutt, K.R., Liang, T.Y., Pasquinelli, A.E., and Yeo, G.W. (2010). Comprehensive discovery of endogenous Argonaute binding sites in Caenorhabditis elegans. Nat. Struct Mol. Biol. 17, 173-179. crossref(new window)