Molecules and Cells

, Volume 31, Issue 6, pp 491–496 | Cite as

The coded functions of noncoding RNAs for gene regulation

  • Sojin An
  • Ji-Joon SongEmail author


For eukaryotes, fine tuning of gene expression is necessary to coordinate complex genetic information. Recent studies have shown that noncoding RNAs (ncRNAs) play central roles in this process. For example, ncRNAs participate in multiple diverse functions such as mRNA degradation, epigenetic regulation and alternative splicing. The findings regarding this new player in gene regulation suggest that the mechanism of gene regulation is much more complicated and subtle than previously thought. In this review, new findings concerning the role of ncRNAs in gene regulation are discussed.


chromatin gene regulation RNA 


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  1. Bies-Etheve, N., Pontier, D., Lahmy, S., Picart, C., Vega, D., Cooke, R., and Lagrange, T. (2009). RNA-directed DNA methylation requires an AGO4-interacting member of the SPT5 elongation factor family. EMBO Rep. 10, 649–654.PubMedCrossRefGoogle Scholar
  2. Blencowe, B.J. (2006). Alternative splicing: new insights from global analyses. Cell 126, 37–47.PubMedCrossRefGoogle Scholar
  3. Borsani, G., Tonlorenzi, R., Simmler, M.C., Dandolo, L., Arnaud, D., Capra, V., Grompe, M., Pizzuti, A., Muzny, D., Lawrence, C., et al. (1991). Characterization of a murine gene expressed from the inactive X chromosome. Nature 351, 325–329.PubMedCrossRefGoogle Scholar
  4. Braidotti, G., Baubec, T., Pauler, F., Seidl, C., Smrzka, O., Stricker, S., Yotova, I., and Barlow, D.P. (2004). The Air noncoding RNA: an imprinted cis-silencing transcript. Cold Spring Harb. Symp. Quant. Biol. 69, 55–66.PubMedCrossRefGoogle Scholar
  5. Brennecke, J., Aravin, A.A., Stark, A., Dus, M., Kellis, M., Sachidanandam, R., and Hannon, G.J. (2007). Discrete small RNAgenerating loci as master regulators of transposon activity in Drosophila. Cell 128, 1089–1103.PubMedCrossRefGoogle Scholar
  6. Brockdorff, N., Ashworth, A., Kay, G.F., Cooper, P., Smith, S., McCabe, V.M., Norris, D.P., Penny, G.D., Patel, D., and Rastan, S. (1991). Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome. Nature 351, 329–331.PubMedCrossRefGoogle Scholar
  7. Brockdorff, N., Ashworth, A., Kay, G.F., McCabe, V.M., Norris, D.P., Cooper, P.J., Swift, S., and Rastan, S. (1992). The product of the mouse Xist gene is a 15 kb inactive X-specific transcript con taining no conserved ORF and located in the nucleus. Cell 71, 515–526.PubMedCrossRefGoogle Scholar
  8. Brower-Toland, B., Findley, S.D., Jiang, L., Liu, L., Yin, H., Dus, M., Zhou, P., Elgin, S.C., and Lin, H. (2007). Drosophila PIWI associates with chromatin and interacts directly with HP1a. Genes Dev. 21, 2300–2311.PubMedCrossRefGoogle Scholar
  9. Brown, C.J., Ballabio, A., Rupert, J.L., Lafreniere, R.G., Grompe, M., Tonlorenzi, R., and Willard, H.F. (1991). A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349, 38–44.PubMedCrossRefGoogle Scholar
  10. Brown, C.J., Hendrich, B.D., Rupert, J.L., Lafreniere, R.G., Xing, Y., Lawrence, J., and Willard, H.F. (1992). The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71, 527–542.PubMedCrossRefGoogle Scholar
  11. Costa, F.F. (2008). Non-coding RNAs, epigenetics and complexity. Gene 410, 9–17.PubMedCrossRefGoogle Scholar
  12. Costanzi, C., Stein, P., Worrad, D.M., Schultz, R.M., and Pehrson, J.R. (2000). Histone macroH2A1 is concentrated in the inactive X chromosome of female preimplantation mouse embryos. Development 127, 2283–2289.PubMedGoogle Scholar
  13. Erhardt, S., Su, I.H., Schneider, R., Barton, S., Bannister, A.J., Perez-Burgos, L., Jenuwein, T., Kouzarides, T., Tarakhovsky, A., and Surani, M.A. (2003). Consequences of the depletion of zygotic and embryonic enhancer of zeste 2 during preimplantation mouse development. Development 130, 4235–4248.PubMedCrossRefGoogle Scholar
  14. Fire, A., Xu, S., Montgomery, M.K., Kostas, S.A., Driver, S.E., and Mello, C.C. (1998). Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811.PubMedCrossRefGoogle Scholar
  15. Girard, A., Sachidanandam, R., Hannon, G.J., and Carmell, M.A. (2006). A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature 442, 199–202.PubMedGoogle Scholar
  16. Grivna, S.T., Pyhtila, B., and Lin, H. (2006). MIWI associates with translational machinery and PIWI-interacting RNAs (piRNAs) in regulating spermatogenesis. Proc. Natl. Acad. Sci. USA 103, 13415–13420.PubMedCrossRefGoogle Scholar
  17. Gunawardane, L.S., Saito, K., Nishida, K.M., Miyoshi, K., Kawamura, Y., Nagami, T., Siomi, H., and Siomi, M.C. (2007). A slicer-mediated mechanism for repeat-associated siRNA 5′ end formation in Drosophila. Science 315, 1587–1590.PubMedCrossRefGoogle Scholar
  18. Hall, I.M., Shankaranarayana, G.D., Noma, K., Ayoub, N., Cohen, A., and Grewal, S.I. (2002). Establishment and maintenance of a heterochromatin domain. Science 297, 2232–2237.PubMedCrossRefGoogle Scholar
  19. Hall, L.L., Smith, K.P., Byron, M., and Lawrence, J.B. (2006). Molecular anatomy of a speckle. Anat. Rec. A Discov. Mol. Cell Evol. Biol. 288, 664–675.PubMedGoogle Scholar
  20. Hannon, G.J. (2002). RNA interference. Nature 418, 244–251.PubMedCrossRefGoogle Scholar
  21. Hutchinson, J.N., Ensminger, A.W., Clemson, C.M., Lynch, C.R., Lawrence, J.B., and Chess, A. (2007). A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains. BMC Genomics 8, 39.PubMedCrossRefGoogle Scholar
  22. Iida, T., Nakayama, J., and Moazed, D. (2008). siRNA-mediated heterochromatin establishment requires HP1 and is associated with antisense transcription. Mol. Cell 31, 178–189.PubMedCrossRefGoogle Scholar
  23. Ji, P., Diederichs, S., Wang, W., Boing, S., Metzger, R., Schneider, P.M., Tidow, N., Brandt, B., Buerger, H., Bulk, E., et al. (2003). MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22, 8031–8041.PubMedCrossRefGoogle Scholar
  24. Kuramochi-Miyagawa, S., Watanabe, T., Gotoh, K., Totoki, Y., Toyoda, A., Ikawa, M., Asada, N., Kojima, K., Yamaguchi, Y., Ijiri, T. W., et al. (2008). DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes. Genes Dev. 22, 908–917.PubMedCrossRefGoogle Scholar
  25. Lamond, A.I., and Spector, D.L. (2003). Nuclear speckles: a model for nuclear organelles. Nat. Rev. Mol. Cell Biol. 4, 605–612.PubMedCrossRefGoogle Scholar
  26. Lau, N.C., Seto, A.G., Kim, J., Kuramochi-Miyagawa, S., Nakano, T., Bartel, D.P., and Kingston, R.E. (2006). Characterization of the piRNA complex from rat testes. Science 313, 363–367.PubMedCrossRefGoogle Scholar
  27. Lee, J.T., and Jaenisch, R. (1997). Long-range cis effects of ectopic X-inactivation centres on a mouse autosome. Nature 386, 275–279.PubMedCrossRefGoogle Scholar
  28. Lee, J.T., and Lu, N. (1999). Targeted mutagenesis of Tsix leads to nonrandom X inactivation. Cell 99, 47–57.PubMedCrossRefGoogle Scholar
  29. Lee, J.T., Davidow, L.S., and Warshawsky, D. (1999). Tsix, a gene antisense to Xist at the X-inactivation centre. Nat. Genet. 21, 400–404.PubMedCrossRefGoogle Scholar
  30. Lin, R., Maeda, S., Liu, C., Karin, M., and Edgington, T.S. (2007). A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene 26, 851–858.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. Long, J.C., and Caceres, J.F. (2009). The SR protein family of splicing factors: master regulators of gene expression. Biochem. J. 417, 15–27.PubMedCrossRefGoogle Scholar
  33. Malone, C.D., Brennecke, J., Dus, M., Stark, A., McCombie, W.R., Sachidanandam, R., and Hannon, G.J. (2009). Specialized piRNA pathways act in germline and somatic tissues of the Drosophila ovary. Cell 137, 522–535.PubMedCrossRefGoogle Scholar
  34. Martin, G.R., Epstein, C.J., Travis, B., Tucker, G., Yatziv, S., Martin, D.W., Jr., Clift, S., and Cohen, S. (1978). X-chromosome inactivation during differentiation of female teratocarcinoma stem cells in vitro. Nature 271, 329–333.PubMedCrossRefGoogle Scholar
  35. Masui, O., and Heard, E. (2006). RNA and protein actors in Xchromosome inactivation. Cold Spring Harb. Symp. Quant. Biol. 71, 419–428.PubMedCrossRefGoogle Scholar
  36. Matzke, M., Matzke, A.J., and Kooter, J.M. (2001). RNA: guiding gene silencing. Science 293, 1080–1083.PubMedCrossRefGoogle Scholar
  37. McCarrey, J.R., and Dilworth, D.D. (1992). Expression of Xist in mouse germ cells correlates with X-chromosome inactivation. Nat. Genet. 2, 200–203.PubMedCrossRefGoogle Scholar
  38. McClintock, B. (1953). Induction of instability at selected loci in maize. Genetics 38, 579–599.PubMedGoogle Scholar
  39. Ogawa, Y., and Lee, J.T. (2003). Xite, X-inactivation intergenic transcription elements that regulate the probability of choice. Mol. Cell 11, 731–743.PubMedCrossRefGoogle Scholar
  40. Okamoto, I., Otte, A.P., Allis, C.D., Reinberg, D., and Heard, E. (2004). Epigenetic dynamics of imprinted X inactivation during early mouse development. Science 303, 644–649.PubMedCrossRefGoogle Scholar
  41. Pal-Bhadra, M., Leibovitch, B.A., Gandhi, S.G., Rao, M., Bhadra, U., Birchler, J.A., and Elgin, S.C. (2004). Heterochromatic silencing and HP1 localization in Drosophila are dependent on the RNAi machinery. Science 303, 669–672.PubMedCrossRefGoogle Scholar
  42. Penny, G.D., Kay, G.F., Sheardown, S.A., Rastan, S., and Brockdorff, N. (1996). Requirement for Xist in X chromosome inactivation. Nature 379, 131–137.PubMedCrossRefGoogle Scholar
  43. Plath, K., Fang, J., Mlynarczyk-Evans, S.K., Cao, R., Worringer, K.A., Wang, H., de la Cruz, C.C., Otte, A.P., Panning, B., and Zhang, Y. (2003). Role of histone H3 lysine 27 methylation in X inactivation. Science 300, 131–135.PubMedCrossRefGoogle Scholar
  44. Plath, K., Talbot, D., Hamer, K.M., Otte, A.P., Yang, T.P., Jaenisch, R., and Panning, B. (2004). Developmentally regulated alterations in Polycomb repressive complex 1 proteins on the inactive X chromosome. J. Cell Biol. 167, 1025–1035.PubMedCrossRefGoogle Scholar
  45. Rank, G., Prestel, M., and Paro, R. (2002). Transcription through intergenic chromosomal memory elements of the Drosophila bithorax complex correlates with an epigenetic switch. Mol. Cell. Biol. 22, 8026–8034.PubMedCrossRefGoogle Scholar
  46. Rastan, S., and Robertson, E.J. (1985). X-chromosome deletions in embryo-derived (EK) cell lines associated with lack of X-chromosome inactivation. J. Embryol. Exp. Morphol. 90, 379–388.PubMedGoogle Scholar
  47. Rinn, J.L., Kertesz, M., Wang, J.K., Squazzo, S.L., Xu, X., Brugmann, S.A., Goodnough, L.H., Helms, J.A., Farnham, P.J., Segal, E., et al. (2007). Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323.PubMedCrossRefGoogle Scholar
  48. Sado, T., Wang, Z., Sasaki, H., and Li, E. (2001). Regulation of imprinted X-chromosome inactivation in mice by Tsix. Development 128, 1275–1286.PubMedGoogle Scholar
  49. Silva, J., Mak, W., Zvetkova, I., Appanah, R., Nesterova, T.B., Webster, Z., Peters, A.H., Jenuwein, T., Otte, A.P., and Brockdorff, N. (2003). Establishment of histone h3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 polycomb group complexes. Dev. Cell 4, 481–495.PubMedCrossRefGoogle Scholar
  50. Song, J.J., Smith, S.K., Hannon, G.J., and Joshua-Tor, L. (2004). Crystal structure of Argonaute and its implications for RISC slicer activity. Science 305, 1434–1437.PubMedCrossRefGoogle Scholar
  51. Sun, B.K., Deaton, A.M., and Lee, J.T. (2006). A transient heterochromatic state in Xist preempts X inactivation choice without RNA stabilization. Mol. Cell 21, 617–628.PubMedCrossRefGoogle Scholar
  52. Sunwoo, H., Dinger, M.E., Wilusz, J.E., Amaral, P.P., Mattick, J.S., and Spector, D.L. (2009). MEN epsilon/beta nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. Genome Res. 19, 347–359.PubMedCrossRefGoogle Scholar
  53. Tano, K., Mizuno, R., Okada, T., Rakwal, R., Shibato, J., Masuo, Y., Ijiri, K., and Akimitsu, N. (2010). MALAT-1 enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility-related genes. FEBS Lett. 584, 4575–4580.PubMedCrossRefGoogle Scholar
  54. Tripathi, V., Ellis, J.D., Shen, Z., Song, D.Y., Pan, Q., Watt, A.T., Freier, S.M., Bennett, C.F., Sharma, A., Bubulya, P.A., et al. (2010). The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol. Cell 39, 925–938.PubMedCrossRefGoogle Scholar
  55. Tsai, M.C., Manor, O., Wan, Y., Mosammaparast, N., Wang, J.K., Lan, F., Shi, Y., Segal, E., and Chang, H.Y. (2010). Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693.PubMedCrossRefGoogle Scholar
  56. Tseng, J.J., Hsieh, Y.T., Hsu, S.L., and Chou, M.M. (2009). Metastasis associated lung adenocarcinoma transcript 1 is upregulated in placenta previa increta/percreta and strongly associated with trophoblast-like cell invasion in vitro. Mol. Hum. Reprod. 15, 725–731.PubMedCrossRefGoogle Scholar
  57. Unhavaithaya, Y., Hao, Y., Beyret, E., Yin, H., Kuramochi-Miyagawa, S., Nakano, T., and Lin, H. (2009). MILI, a PIWI-interacting RNA-binding protein, is required for germ line stem cell self-renewal and appears to positively regulate translation. J. Biol. Chem. 284, 6507–6519.PubMedCrossRefGoogle Scholar
  58. Volpe, T.A., Kidner, C., Hall, I.M., Teng, G., Grewal, S.I., and Martienssen, R.A. (2002). Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297, 1833–1837.PubMedCrossRefGoogle Scholar
  59. White, W.M., Willard, H.F., Van Dyke, D.L., and Wolff, D.J. (1998). The spreading of X inactivation into autosomal material of an x;autosome translocation: evidence for a difference between autosomal and X-chromosomal DNA. Am. J. Hum. Genet. 63, 20–28.PubMedCrossRefGoogle Scholar
  60. Wilusz, J.E., Freier, S.M., and Spector, D.L. (2008). 3′ end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell 135, 919–932.PubMedCrossRefGoogle Scholar
  61. Woo, C.J., and Kingston, R.E. (2007). HOTAIR lifts noncoding RNAs to new levels. Cell 129, 1257–1259.PubMedCrossRefGoogle Scholar
  62. Wutz, A., and Jaenisch, R. (2000). A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. Mol. Cell 5, 695–705.PubMedCrossRefGoogle Scholar
  63. Yin, H., and Lin, H. (2007). An epigenetic activation role of Piwi and a Piwi-associated piRNA in Drosophila melanogaster. Nature 450, 304–308.PubMedCrossRefGoogle Scholar

Copyright information

© The Korean Society for Molecular and Cellular Biology and Springer Netherlands 2011

Authors and Affiliations

  1. 1.Structural Biology Laboratory of Epigenetics, Department of Biological Sciences, Graduate School of Nanoscience and Technology (World Class University)KI Institute for the BioCentury, Korea Advanced Institute of Science and TechnologyDaejeonKorea

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