Key Points
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MicroRNA (miRNA) genes encode long primary RNA transcripts that are processed into a precursor miRNA (pre-miRNA) that is ∼60 nucleotides in length. The pre-miRNA is then further processed to provide the mature miRNA.
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Mature miRNAs are ∼22-nucleotide small non-coding RNAs that are thought to regulate gene expression at the post-transcriptional level by targeting mRNA for degradation or translational repression.
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Systematic cloning and computational predictions indicate that there are hundreds of miRNA genes in animals; humans may have as many as one thousand miRNA genes.
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Some primary miRNAs are synthesized by RNA polymerase II and have 5′ caps and 3′ poly(A) tails, whereas others might be transcribed by RNA polymerase III.
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Some of the protein machinery that processes primary transcripts into pre-miRNAs and mature miRNAs is also used in the RNA interference (RNAi) pathways and is functionally important for animal development.
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The expression of miRNAs is temporally and spatially regulated during animal development. Some miRNAs are differentially expressed during haematopoietic lineage differentiation.
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Computational analyses have shown that miRNAs may regulate over one-third of the protein-coding genes in the human genome.
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miRNAs have important roles in regulating the development and function of immune cells.
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Altered miRNA levels are associated with various cancers, including leukaemias and lymphomas.
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Mice deficient for miR-155 are immunodeficient, and have defects in the function of B cells, T cells and dendritic cells, as well as in the development of T helper cells and germinal centres.
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miR-181a could function as an antigen sensitivity rheostat to modulate T-cell sensitivity to antigens during T-cell development and maturation by downregulating the expression of multiple phosphatases in the T-cell receptor signalling pathway.
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Viral genomes encode miRNAs that are used to regulate viral and host gene expression and modulate the function of host immune cells.
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Host miRNAs may be used to target viral genome to either repress or potentiate viral replication.
Abstract
MicroRNAs (miRNAs) are an abundant class of evolutionarily conserved small non-coding RNAs that are thought to control gene expression by targeting mRNAs for degradation or translational repression. Emerging evidence suggests that miRNA-mediated gene regulation represents a fundamental layer of genetic programmes at the post-transcriptional level and has diverse functional roles in animals. Here, we provide an overview of the mechanisms by which miRNAs regulate gene expression, with specific focus on the role of miRNAs in regulating the development of immune cells and in modulating innate and adaptive immune responses.
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References
Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004). A comprehensive review that describes the genomics, biogenesis and mechanism of action of miRNAs.
Bartel, D. P. & Chen, C. Z. Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nature Rev. Genet. 5, 396–400 (2004).
Bushati, N. & Cohen, S. M. microRNA functions. Annu. Rev. Cell Dev. Biol. 23, 175–205 (2007).
Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993). Reference 4 is a hallmark paper that describes the identification of the lin-4 miRNA gene, the first example of an miRNA gene, and shows that it has a crucial role in regulating the timing of lineage differentiation in C. elegans.
Wightman, B., Ha, I. & Ruvkun, G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75, 855–862 (1993). Reference 5 is a hallmark paper showing that the heterochronic gene lin-14 is regulated by lin-4 miRNA at the post-transcriptional level in C. elegans.
Reinhart, B. J. et al. The 21 nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901–906 (2000).
Slack, F. J. et al. The lin-41 RBCC gene acts in the C. elegans heterochronic pathway between the let-7 regulatory RNA and the LIN-29 transcription factor. Mol. Cell 5, 659–669 (2000).
Pasquinelli, A. E. et al. Conservation across animal phylogeny of the sequence and temporal regulation of the 21 nucleotide let-7 heterochronic regulatory RNA. Nature 408, 86–89 (2000).
Johnston, R. J. & Hobert, O. A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans. Nature 426, 845–849 (2003).
Brennecke, J., Hipfner, D. R., Stark, A., Russell, R. B. & Cohen, S. M. bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113, 25–36 (2003).
Xu, P., Vernooy, S. Y., Guo, M. & Hay, B. A. The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism. Curr. Biol. 13, 790–795 (2003).
Lau, N. C., Lim, L. P., Weinstein, E. G. & Bartel, D. P. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294, 858–862 (2001).
Lee, R. C. & Ambros, V. An extensive class of small RNAs in Caenorhabditis elegans. Science 294, 862–864 (2001).
Lagos-Quintana, M., Rauhut, R., Lendeckel, W. & Tuschl, T. Identification of novel genes coding for small expressed RNAs. Science 294, 853–858 (2001).
Lagos-Quintana, M. et al. Identification of tissue-specific microRNAs from mouse. Curr. Biol. 12, 735–739 (2002).
Lim, L. P., Glasner, M. E., Yekta, S., Burge, C. B. & Bartel, D. P. Vertebrate microRNA genes. Science 299, 1540 (2003).
Lim, L. P. et al. The microRNAs of Caenorhabditis elegans. Genes Dev. 17, 991–1008 (2003).
Bentwich, I. et al. Identification of hundreds of conserved and nonconserved human microRNAs. Nature Genet. 37, 766–770 (2005).
Miranda, K. C. et al. A pattern-based method for the identification of microRNA binding sites and their corresponding heteroduplexes. Cell 126, 1203–1217 (2006).
Landgraf, P. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401–1414 (2007).
Berezikov, E. et al. Phylogenetic shadowing and computational identification of human microRNA genes. Cell 120, 21–24 (2005).
Griffiths-Jones, S. The microRNA registry. Nucleic Acids Res. 32, D109–D111 (2004).
Ruby, J. G. et al. Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans. Cell 127, 1193–1207 (2006).
Chen, X. M., Splinter, P. L., O'Hara S, P. & Larusso, N. F. A cellular micro-RNA, let-7i, regulates Toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection. J. Biol. Chem. 282, 28929–28938 (2007).
Altuvia, Y. et al. Clustering and conservation patterns of human microRNAs. Nucleic Acids Res. 33, 2697–2706 (2005).
Megraw, M., Sethupathy, P., Corda, B. & Hatzigeorgiou, A. G. miRGen: a database for the study of animal microRNA genomic organization and function. Nucleic Acids Res. 35, D149–D155 (2007).
Kim, V. N. MicroRNA biogenesis: coordinated cropping and dicing. Nature Rev. Mol. Cell Biol. 6, 376–385 (2005).
Lee, Y. et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23, 4051–4060 (2004).
Cai, X., Hagedorn, C. H. & Cullen, B. R. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 10, 1957–1966 (2004).
Borchert, G. M., Lanier, W. & Davidson, B. L. RNA polymerase III transcribes human microRNAs. Nature Struct. Mol. Biol. 13, 1097–1101 (2006).
Lee, Y. et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415–419 (2003).
Denli, A. M., Tops, B. B., Plasterk, R. H., Ketting, R. F. & Hannon, G. J. Processing of primary microRNAs by the microprocessor complex. Nature 432, 231–235 (2004).
Landthaler, M., Yalcin, A. & Tuschl, T. The human DiGeorge syndrome critical region gene 8 and its D. melanogaster homolog are required for miRNA biogenesis. Curr. Biol. 14, 2162–2167 (2004).
Han, M. H., Goud, S., Song, L. & Fedoroff, N. The Arabidopsis double-stranded RNA-binding protein HYL1 plays a role in microRNA-mediated gene regulation. Proc. Natl Acad. Sci. USA 101, 1093–1098 (2004).
Okamura, K., Hagen, J. W., Duan, H., Tyler, D. M. & Lai, E. C. The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell 130, 89–100 (2007).
Ruby, J. G., Jan, C. H. & Bartel, D. P. Intronic microRNA precursors that bypass Drosha processing. Nature 448, 83–86 (2007).
Hammond, S. C., Bernstein, E., Beach, D. & Hannon, G. J. An RNA-directed nuclease mediates posttranscriptional gene silencing in Drosophila cells. Nature 404, 293–296 (2000).
Bernstein, E., Caudy, A. A., Hammond, S. M. & Hannon, G. J. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409, 295–296 (2001).
Lee, Y., Jeon, K., Lee, J. T., Kim, S. & Kim, V. N. MicroRNA maturation: stepwise processing and subcellular localization. EMBO J. 21, 4663–4670 (2002).
Yi, R., Qin, Y., Macara, I. G. & Cullen, B. R. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 17, 3011–3016 (2003).
Bohnsack, M. T., Czaplinski, K. & Gorlich, D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 10, 185–191 (2004).
Lund, E., Guttinger, S., Calado, A., Dahlberg, J. E. & Kutay, U. Nuclear export of microRNA precursors. Science 303, 95–98 (2004).
Lingel, A., Simon, B., Izaurralde, E. & Sattler, M. Structure and nucleic-acid binding of the Drosophila Argonaute 2 PAZ domain. Nature 426, 465–469 (2003).
Liu, J. et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437–1441 (2004).
Chen, C. Z., Li, L., Lodish, H. F. & Bartel, D. P. MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004). This paper describes the identification of miRNAs that are differentially expressed during haematopoietic-lineage differentiation and shows that miR-181a can modulate B- and T-cell differentiation, providing the first example of miRNA function in vertebrate cells.
Zeng, Y. & Cullen, B. R. Structural requirements for pre-microRNA binding and nuclear export by Exportin 5. Nucleic Acids Res. 32, 4776–4785 (2004).
Zeng, Y. & Cullen, B. R. Efficient processing of primary microRNA hairpins by Drosha requires flanking nonstructured RNA sequences. J. Biol. Chem. 280, 27595–27603 (2005).
Zeng, Y., Yi, R. & Cullen, B. R. Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha. EMBO J. 24, 138–148 (2005).
Zeng, Y., Cai, X. & Cullen, B. R. Use of RNA polymerase II to transcribe artificial microRNAs. Methods Enzymol. 392, 371–380 (2005).
Wulczyn, F. G. et al. Post-transcriptional regulation of the let-7 microRNA during neural cell specification. FASEB J. 21, 415–426 (2007).
Thomson, J. M. et al. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 20, 2202–2207 (2006).
Nilsen, T. W. Mechanisms of microRNA-mediated gene regulation in animal cells. Trends Genet. 23, 243–249 (2007).
Lim, L. P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769–773 (2005).
Pillai, R. S., Bhattacharyya, S. N. & Filipowicz, W. Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell. Biol. 17, 118–126 (2007).
Jackson, R. J. & Standart, N. How do microRNAs regulate gene expression? Sci. STKE 367, re1 (2007).
Olsen, P. H. & Ambros, V. The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. Dev. Biol. 216, 671–680 (1999).
Seggerson, K., Tang, L. & Moss, E. G. Two genetic circuits repress the Caenorhabditis elegans heterochronic gene lin-28 after translation initiation. Dev. Biol. 243, 215–225 (2002).
Maroney, P. A., Yu, Y., Fisher, J. & Nilsen, T. W. Evidence that microRNAs are associated with translating messenger RNAs in human cells. Nature Struct. Mol. Biol. 13, 1102–1107 (2006).
Nottrott, S., Simard, M. J. & Richter, J. D. Human let-7a miRNA blocks protein production on actively translating polyribosomes. Nature Struct. Mol. Biol. 13, 1108–1114 (2006).
Pillai, R. S. et al. Inhibition of translational initiation by Let-7 MicroRNA in human cells. Science 309, 1573–1576 (2005).
Wakiyama, M., Takimoto, K., Ohara, O. & Yokoyama, S. Let-7 microRNA-mediated mRNA deadenylation and translational repression in a mammalian cell-free system. Genes Dev. 21, 1857–1862 (2007).
Mathonnet, G. et al. MicroRNA inhibition of translation initiation in vitro by targeting the cap-binding complex eIF4F. Science 317, 1764–1767 (2007).
Thermann, R. & Hentze, M. W. Drosophila miR2 induces pseudo-polysomes and inhibits translation initiation. Nature 447, 875–878 (2007).
Kiriakidou, M. et al. An mRNA m7G cap binding-like motif within human Ago2 represses translation. Cell 129, 1141–1151 (2007).
Lai, E. C. MicroRNAs are complementary to 3′UTR motifs that mediate negative post-transcriptional regulation. Nature Genet. 30, 363–364 (2002).
Lewis, B. P., Shih, I. H., Jones-Rhoades, M. W., Bartel, D. P. & Burge, C. B. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003). This is one of the first reports on computational prediction of miRNA target genes. It shows that seed nucleotides, which are the 5′ 2–8 nucleotides of a mature miRNA, are crucial for computational target gene prediction.
Stark, A., Brennecke, J., Russell, R. B. & Cohen, S. M. Identification of Drosophila microRNA targets. PLoS Biol. 1, E60 (2003).
O'Donnell, K. A., Wentzel, E. A., Zeller, K. I., Dang, C. V. & Mendell, J. T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839–843 (2005).
Rajewsky, N. microRNA target predictions in animals. Nature Genet. 38, S8–S13 (2006). This is a comprehensive review that describes the computational methods for miRNA target gene prediction.
Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).
Grimson, A. et al. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol. Cell 27, 91–105 (2007).
Enright, A. J. et al. MicroRNA targets in Drosophila. Genome Biol. 5, R1 (2003).
John, B. et al. Human microRNA targets. PLoS Biol. 2, e363 (2004).
Rajewsky, N. & Socci, N. D. Computational identification of microRNA targets. Dev. Biol. 267, 529–535 (2004).
Krek, A. et al. Combinatorial microRNA target predictions. Nature Genet. 37, 495–500 (2005).
Farh, K. K. et al. The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science 310, 1817–1821 (2005).
Stark, A., Brennecke, J., Bushati, N., Russell, R. B. & Cohen, S. M. Animal microRNAs confer robustness to gene expression and have a significant impact on 3′UTR evolution. Cell 123, 1133–1146 (2005).
Lytle, J. R., Yario, T. A. & Steitz, J. A. Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc. Natl Acad. Sci. USA 104, 9667–9672 (2007).
Chang, S., Johnston, R. J. Jr, Frokjaer-Jensen, C., Lockery, S. & Hobert, O. MicroRNAs act sequentially and asymmetrically to control chemosensory laterality in the nematode. Nature 430, 785–789 (2004).
Didiano, D. & Hobert, O. Perfect seed pairing is not a generally reliable predictor for miRNA-target interactions. Nature Struct. Mol. Biol. 13, 849–851 (2006).
Vella, M. C., Choi, E. Y., Lin, S. Y., Reinert, K. & Slack, F. J. The C. elegans microRNA let-7 binds to imperfect let-7 complementary sites from the lin-41 3′UTR. Genes Dev. 18, 132–137 (2004).
Vella, M. C., Reinert, K. & Slack, F. J. Architecture of a validated microRNA::target interaction. Chem. Biol. 11, 1619–1623 (2004).
Long, D. et al. Potent effect of target structure on microRNA function. Nature Struct. Mol. Biol. 14, 287–294 (2007).
Plasterk, R. H. Micro RNAs in animal development. Cell 124, 877–881 (2006).
Zhao, Y. et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129, 303–317 (2007).
Rodriguez, A. et al. Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611 (2007). This report shows that mice deficient in miR-155 are immunodeficient, and have defects in the function of B and T cells, as well as dendritic cells.
Thai, T. H. et al. Regulation of the germinal center response by microRNA-155. Science 316, 604–608 (2007). Using gain-of-function and lost-of-function analyses in mice, this study demonstrates an important role for miRNA-155 in the differentiation of T helper cells and the establishment of germinal centres.
van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007).
Calin, G. A. et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc. Natl Acad. Sci. USA 101, 11755–11760 (2004).
Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).
Garzon, R., Fabbri, M., Cimmino, A., Calin, G. A. & Croce, C. M. MicroRNA expression and function in cancer. Trends Mol. Med. 12, 580–587 (2006).
Esquela-Kerscher, A. & Slack, F. J. Oncomirs — microRNAs with a role in cancer. Nature Rev. Cancer 6, 259–269 (2006).
Monticelli, S. et al. MicroRNA profiling of the murine hematopoietic system. Genome Biol. 6, R71 (2005).
Ramkissoon, S. H. et al. Hematopoietic-specific microRNA expression in human cells. Leuk. Res. 30, 643–647 (2006).
Choong, M. L., Yang, H. H. & McNiece, I. MicroRNA expression profiling during human cord blood-derived CD34 cell erythropoiesis. Exp. Hematol. 35, 551–564 (2007).
Neilson, J. R., Zheng, G. X., Burge, C. B. & Sharp, P. A. Dynamic regulation of miRNA expression in ordered stages of cellular development. Genes Dev. 21, 578–589 (2007). This report describes the systematic cloning of miRNAs from purified T-cell populations, and should be a useful resource for studying miRNAs that may have roles during T-cell development.
Wu, H., Neilson, J. R., Kumar, P., Manocha, M., Shankar, P., Sharp, P. A. & Manjunath, N. miRNA profiling of naive, effector, and memory CD8 T cells. PLoS ONE 2, e1020 (2007).
Zheng, Y. et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445, 936–940 (2007).
Li, Q. J. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147–161 (2007). This study shows that miR-181a can function as an antigen sensitivity rheostat to modulate T-cell sensitivity to antigens during T-cell development and maturation by downregulating the expression of multiple phosphatases in the TCR signalling pathway.
Zhou, B., Wang, S., Mayr, C., Bartel, D. P. & Lodish, H. F. miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely. Proc. Natl Acad. Sci. USA 104, 7080–7085 (2007).
Daley, G. Q., Van Etten, R. A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247, 824–830. (1990).
Fazi, F. et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPα regulates human granulopoiesis. Cell 123, 819–831 (2005).
Fukao, T. et al. An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling. Cell 129, 617–631 (2007).
Xiao, C. et al. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 131, 146–159 (2007). Using both gain- and loss-of-function analyses in mice, this study demonstrates the important role of miR-150 in B-cell development through targeting Myb.
Tam, W., Ben-Yehuda, D. & Hayward, W. S. bic, a novel gene activated by proviral insertions in avian leukosis virus-induced lymphomas, is likely to function through its noncoding RNA. Mol. Cell. Biol. 17, 1490–1502 (1997).
Eis, P. S. et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc. Natl Acad. Sci. USA 102, 3627–3632 (2005).
Kluiver, J. et al. BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J. Pathol. 207, 243–249 (2005).
Metzler, M., Wilda, M., Busch, K., Viehmann, S. & Borkhardt, A. High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma. Genes Chromosomes Cancer 39, 167–169 (2004).
Tam, W. & Dahlberg, J. E. miR-155/BIC as an oncogenic microRNA. Genes Chromosomes Cancer 45, 211–212 (2006).
Costinean, S. et al. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in Eμ-miR155 transgenic mice. Proc. Natl Acad. Sci. USA 103, 7024–7029 (2006).
Davey, G. M. et al. Preselection thymocytes are more sensitive to T cell receptor stimulation than mature T cells. J. Exp. Med. 188, 1867–1874 (1998).
Pircher, H., Rohrer, U. H., Moskophidis, D., Zinkernagel, R. M. & Hengartner, H. Lower receptor avidity required for thymic clonal deletion than for effector T-cell function. Nature 351, 482–485 (1991).
Hogquist, K. A., Jameson, S. C. & Bevan, M. J. The ligand for positive selection of T lymphocytes in the thymus. Curr. Opin. Immunol. 6, 273–278 (1994).
Taganov, K. D., Boldin, M. P., Chang, K. J. & Baltimore, D. NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl Acad. Sci. USA 103, 12481–12486 (2006).
O'Connell, R. M., Taganov, K. D., Boldin, M. P., Cheng, G. & Baltimore, D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc. Natl Acad. Sci. USA 104, 1604–1609 (2007).
Lecellier, C. H. et al. A cellular microRNA mediates antiviral defense in human cells. Science 308, 557–560 (2005). This paper demonstrates that the cellular miRNA miR-32 can effectively limit replication of PFV1, and a suppressor protein encoded by the virus can counteract the repressive effect of miR-32 in a plant system.
Pedersen, I. M. et al. Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449, 919–921 (2007). This report shows that the IFN signalling system, the key defence mechanism against viral infection in mammalian cells, works in concert with miRNAs to control viral infection.
Jopling, C. L., Yi, M., Lancaster, A. M., Lemon, S. M. & Sarnow, P. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science 309, 1577–1581 (2005). This paper shows that the host miRNA miR-122 could be used by HCV to potentiate HCV replication.
Lu, R. et al. Animal virus replication and RNAi-mediated antiviral silencing in Caenorhabditis elegans. Nature 436, 1040–1043 (2005).
Li, H., Li, W. X. & Ding, S. W. Induction and suppression of RNA silencing by an animal virus. Science 296, 1319–1321 (2002). This study shows that flock house virus (FHV) encodes an RNAi suppressor protein, B2, which is required for the FHV infection of D. melanogaster host cells, indicating the importance of RNA interference pathway in antiviral defence in flies.
Sarnow, P., Jopling, C. L., Norman, K. L., Schutz, S. & Wehner, K. A. MicroRNAs: expression, avoidance and subversion by vertebrate viruses. Nature Rev. Microbiol. 4, 651–659 (2006).
Pfeffer, S. et al. Identification of virus-encoded microRNAs. Science 304, 734–736 (2004). This is the first study to show that DNA viruses encode miRNAs.
Pfeffer, S. et al. Identification of microRNAs of the herpesvirus family. Nature Methods 2, 269–276 (2005).
Sullivan, C. S., Grundhoff, A. T., Tevethia, S., Pipas, J. M. & Ganem, D. SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells. Nature 435, 682–686 (2005). This report demonstrates that virus-encoded miRNAs could regulate SV40-encoded mRNAs and facilitate viral infection.
Cai, X. et al. Kaposi's sarcoma-associated herpesvirus expresses an array of viral microRNAs in latently infected cells. Proc. Natl Acad. Sci. USA 102, 5570–5575 (2005).
Gupta, A., Gartner, J. J., Sethupathy, P., Hatzigeorgiou, A. G. & Fraser, N. W. Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript. Nature 442, 82–85 (2006).
Stern-Ginossar, N. et al. Host immune system gene targeting by a viral miRNA. Science 317, 376–381 (2007).
Triboulet, R. et al. Suppression of microRNA-silencing pathway by HIV-1 during virus replication. Science 315, 1579–1582 (2007).
Bennasser, Y. & Jeang, K. T. HIV-1 Tat interaction with Dicer: requirement for RNA. Retrovirology 3, 95 (2006).
Metcalf, D. & Nicola, NA. The hematopoietic colony-stimulating factors. From biology to clinical applications. (Cambridge Univ. Press, 1995).
Shivdasani, R. A. & Orkin, S. H. The transcriptional control of hematopoiesis. Blood 87, 4025–4039 (1996).
Zheng, Y. et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445, 936–940 (2007).
Raveche, E. S. et al. Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice. Blood 109, 5079–5086 (2007).
Lian, S. et al. GW bodies, microRNAs and the cell cycle. Cell Cycle 5, 242–245 (2006).
Gregory, R. I. et al. The microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004).
Gregory, R. I., Chendrimada, T. P., Cooch, N. & Shiekhattar, R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell 123, 631–640 (2005).
Haase, A. D. et al. TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing. EMBO Rep. 6, 961–967 (2005).
Chendrimada, T. P. et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436, 740–744 (2005).
Acknowledgements
We thank members of the Chen and Lodish laboratories and also V. Ambros for his helpful comments on this manuscript. This research on miRNAs is supported by grants 1R01HL081612-01 to C.-Z. C. and 5R01DK068348 to H.F.L.
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Glossary
- Forward genetics
-
A classical genetic analysis approach that proceeds from phenotype to genotype by positional cloning or candidate-gene analysis.
- RNA-induced silencing complex
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(RISC). A multi-protein small interfering RNA (siRNA) complex that binds short antisense RNA strands and guides the cleavage of target RNAs. This complex is thought to be important for post-transcriptional gene regulation by siRNAs and microRNAs.
- Microarray analysis
-
A technique for measuring the transcription of genes. It involves hybridization of fluorescently labelled cDNA prepared from a cell or tissue of interest with glass slides or other surfaces dotted with thousands of oligonucleotides or cDNA, ideally representing all expressed genes in the species.
- Polysome profile
-
Polysomes (or polyribosomes) are a cluster of ribosomes that are attached along the length of a single molecule of mRNA. Polysomes read this mRNA simultaneously, helping to synthesize the same protein at different spots on the mRNA. A polysome profile refers to the distribution of polysomes as determined by gradient centrifugation of cytoplasmic extracts. The method is used to study the association of mRNAs with ribosomes.
- m7G cap
-
The 7-methylguanosine that is linked by a triphosphate bridge to the first transcribed nucleotide at the 5′ end of eukaryotic mRNA. Recognition of the m7G cap by the cap-binding protein eIF4E is the initiation step of cap-dependent translation.
- Argonaute (AGO) proteins
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A large family of ∼95 KDa proteins that contain conserved PAZ (piwi, argonaut and zwille) and PIWI domains and are involved in post-transcriptional gene silencing. Mammals have four AGO family members (AGO1, AGO2, AGO3 and AGO4), each of which might be a component of an RNA-induced silencing complex.
- Seed nucleotides
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This term refers to the seven nucleotides found at the 5′ region of an miRNA (nucleotides 2–8). Many computational target prediciton programmes require an exact Watson–Crick complementary match between the target sites and the seed nucleotides of a mature miRNA.
- Small interfering RNAs
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(siRNAs). A class of double-stranded RNAs (dsRNAs) of ∼21 nucleotides in length, generated from long dsRNAs. siRNAs silence gene expression by promoting the cleavage of perfectly matched mRNAs. siRNAs can also be generated by in vitro synthesis and can be used to 'knockdown' (that is, to silence the expression of) a specific gene.
- Chromatin immunoprecipitation
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(ChIP). The use of antibodies specific for transcription factors to precipitate nucleic-acid sequences from chromatin for amplification.
- B-1 cells
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IgMhiIgDlowMac1+B220lowCD23- cells that are dominant in the peritoneal and pleural cavities. Their precursors develop in the fetal liver and omentum, and in adult mice, the size of the B-1-cell population is kept constant owing to the self-renewing capacity of these cells. B-1 cells recognize self components, as well as common bacterial antigens, and they secrete antibodies that tend to have low affinity and broad specificity.
- RNA interference
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A mechanism for RNA-guided regulation of gene silencing in which double-stranded RNA inhibits the expression of genes with complementary nucleotide sequences.
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Lodish, H., Zhou, B., Liu, G. et al. Micromanagement of the immune system by microRNAs. Nat Rev Immunol 8, 120–130 (2008). https://doi.org/10.1038/nri2252
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DOI: https://doi.org/10.1038/nri2252
