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Chromatin Regulation by Long Non-coding RNAs

  • Daniel C. Factor
  • Paul J. Tesar
  • Ahmad M. Khalil
Chapter

Abstract

After the discovery of thousands of long noncoding RNAs (lncRNAs) in the mammalian genome, it became evident that hundreds of these transcripts are associated with chromatin-modifying complexes across multiple and distinct cell types. Furthermore, a number of lncRNAs have been shown to guide and tether chromatin-modifying complexes to specific genomic loci both in cis and in trans. These exciting findings suggest a general mechanism of lncRNA-mediated chromatin formation in mammals. In this chapter, we will discuss evidence supporting a model that lncRNAs provide the targeting specificity of specific protein complexes to chromatin.

Keywords

Noncoding RNAs Chromatin State Imprint Control Region Natural Antisense Transcript HOXD Cluster 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Banfai, B., Jia, H., Khatun, J., Wood, E., Risk, B., Gundling, W. E, Jr, et al. (2012). Long noncoding RNAs are rarely translated in two human cell lines. Genome Research, 22, 1646–1657.PubMedCrossRefGoogle Scholar
  2. Barr, M. L., & Bertram, E. G. (1949). A morphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis. Nature, 163, 676.PubMedCrossRefGoogle Scholar
  3. Bernstein, B. E., Kamal, M., Lindblad-Toh, K., Bekiranov, S., Bailey, D. K., Huebert, D. J., et al. (2005). Genomic maps and comparative analysis of histone modifications in human and mouse. Cell, 120, 169–181.PubMedCrossRefGoogle Scholar
  4. Bernstein, B. E., Meissner, A., & Lander, E. S. (2007). The mammalian epigenome. Cell, 128, 669–681.PubMedCrossRefGoogle Scholar
  5. Bertani, S., Sauer, S., Bolotin, E., & Sauer, F. (2011). The noncoding RNA Mistral activates Hoxa6 and Hoxa7 expression and stem cell differentiation by recruiting MLL1 to chromatin. Molecular Cell, 43, 1040–1046.PubMedCrossRefGoogle Scholar
  6. Bertone, P., Stolc, V., Royce, T. E., Rozowsky, J. S., Urban, A. E., Zhu, X., et al. (2004). Global identification of human transcribed sequences with genome tiling arrays. Science, 306, 2242–2246.PubMedCrossRefGoogle Scholar
  7. Birney, E., Stamatoyannopoulos, J. A., Dutta, A., Guigo, R., Gingeras, T. R., Margulies, E. H., et al. (2007). Identification and analysis of functional elements in 1 % of the human genome by the ENCODE pilot project. Nature, 447, 799–816.PubMedCrossRefGoogle Scholar
  8. Boyle, A. P., Davis, S., Shulha, H. P., Meltzer, P., Margulies, E. H., Weng, Z., et al. (2008). High-resolution mapping and characterization of open chromatin across the genome. Cell, 132, 311–322.PubMedCrossRefGoogle Scholar
  9. Brockdorff, N., Ashworth, A., Kay, G. F., McCabe, V. M., Norris, D. P., Cooper, P. J., Swift, S., & Rastan, S. (1992). The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71, 515–526.Google Scholar
  10. Brown, C. J., Hendrich, B. D., Rupert, J. L., Lafreniere, R. G., Xing, Y., Lawrence, J., et al. (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. Cabili, M. N., Trapnell, C., Goff, L., Koziol, M., Tazon-Vega, B., Regev, A., et al. (2011). Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes & Development, 25, 1915–1927.CrossRefGoogle Scholar
  12. Carninci, P., Kasukawa, T., Katayama, S., Gough, J., Frith, M. C., Maeda, N., et al. (2005). The transcriptional landscape of the mammalian genome. Science, 309, 1559–1563.PubMedCrossRefGoogle Scholar
  13. Carrel, L., & Willard, H. F. (2005). X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature, 434, 400–404.PubMedCrossRefGoogle Scholar
  14. Chang, H. Y. (2009). Anatomic demarcation of cells: Genes to patterns. Science, 326, 1206–1207.PubMedCrossRefGoogle Scholar
  15. Chu, C., Qu, K., Zhong, F. L., Artandi, S. E., & Chang, H. Y. (2011). Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. Molecular Cell, 44, 667–678.PubMedCrossRefGoogle Scholar
  16. Clark, M. B., & Mattick, J. S. (2011). Long noncoding RNAs in cell biology. Seminars in Cell & Developmental Biology, 22, 366–376.CrossRefGoogle Scholar
  17. Clemson, C. M., McNeil, J. A., Willard, H. F., & Lawrence, J. B. (1996). XIST RNA paints the inactive X chromosome at interphase: Evidence for a novel RNA involved in nuclear/chromosome structure. The Journal of cell biology, 132, 259–275.PubMedCrossRefGoogle Scholar
  18. De Santa, F., Barozzi, I., Mietton, F., Ghisletti, S., Polletti, S., Tusi, B. K., et al. (2010). A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biology, 8, e1000384.PubMedCrossRefGoogle Scholar
  19. Derrien, T., Johnson, R., Bussotti, G., Tanzer, A., Djebali, S., Tilgner, H., et al. (2012). The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression. Genome Research, 22, 1775–1789.PubMedCrossRefGoogle Scholar
  20. Djebali, S., Davis, C. A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., et al. (2012). Landscape of transcription in human cells. Nature, 489, 101–108.PubMedCrossRefGoogle Scholar
  21. Feng, J., Bi, C., Clark, B. S., Mady, R., Shah, P., & Kohtz, J. D. (2006). The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes & Development, 20, 1470–1484.CrossRefGoogle Scholar
  22. Grabherr, M. G., Haas, B. J., Yassour, M., Levin, J. Z., Thompson, D. A., Amit, I., et al. (2011). Full-length transcriptome assembly from RNA-Seq data without a reference genome. Nature Biotechnology, 29, 644–652.PubMedCrossRefGoogle Scholar
  23. Guil, S., Soler, M., Portela, A., Carrere, J., Fonalleras, E., Gomez, A., et al. (2012). Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nature Structural & Molecular Biology, 19, 664–670.CrossRefGoogle Scholar
  24. Gupta, R. A., Shah, N., Wang, K. C., Kim, J., Horlings, H. M., Wong, D. J., et al. (2010). Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature, 464, 1071–1076.PubMedCrossRefGoogle Scholar
  25. Guttman, M., Amit, I., Garber, M., French, C., Lin, M. F., Feldser, D., et al. (2009). Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature, 458, 223–227.PubMedCrossRefGoogle Scholar
  26. Guttman, M., Donaghey, J., Carey, B. W., Garber, M., Grenier, J. K., Munson, G., et al. (2011). lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature, 477, 295–300.PubMedCrossRefGoogle Scholar
  27. Guttman, M., Garber, M., Levin, J. Z., Donaghey, J., Robinson, J., Adiconis, X., et al. (2010). Ab initio reconstruction of cell type-specific transcriptomes in mouse reveals the conserved multi-exonic structure of lincRNAs. Nature Biotechnology, 28, 503–510.PubMedCrossRefGoogle Scholar
  28. He, Y., Vogelstein, B., Velculescu, V. E., Papadopoulos, N., & Kinzler, K. W. (2008). The antisense transcriptomes of human cells. Science, 322, 1855–1857.PubMedCrossRefGoogle Scholar
  29. Heard, E. (2004). Recent advances in X-chromosome inactivation. Current Opinion in Cell Biology, 16, 247–255.PubMedCrossRefGoogle Scholar
  30. Heintzman, N. D., Hon, G. C., Hawkins, R. D., Kheradpour, P., Stark, A., Harp, L. F., et al. (2009). Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature, 459, 108–112.PubMedCrossRefGoogle Scholar
  31. Heintzman, N. D., Stuart, R. K., Hon, G., Fu, Y., Ching, C. W., Hawkins, R. D., et al. (2007). Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nature Genetics, 39, 311–318.PubMedCrossRefGoogle Scholar
  32. Howald, C., Tanzer, A., Chrast, J., Kokocinski, F., Derrien, T., Walters, N., et al. (2012). Combining RT-PCR-seq and RNA-seq to catalog all genic elements encoded in the human genome. Genome Research, 22, 1698–1710.PubMedCrossRefGoogle Scholar
  33. Huarte, M., Guttman, M., Feldser, D., Garber, M., Koziol, M. J., Kenzelmann-Broz, D., et al. (2010). A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell, 142, 409–419.PubMedCrossRefGoogle Scholar
  34. Ingolia, N. T., Lareau, L. F., & Weissman, J. S. (2011). Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell, 147, 789–802.PubMedCrossRefGoogle Scholar
  35. Jan, C. H., Friedman, R. C., Ruby, J. G., & Bartel, D. P. (2011). Formation, regulation and evolution of Caenorhabditis elegans 3′UTRs. Nature, 469, 97–101.PubMedCrossRefGoogle Scholar
  36. Kanhere, A., Viiri, K., Araujo, C. C., Rasaiyaah, J., Bouwman, R. D., Whyte, W. A., et al. (2010). Short RNAs are transcribed from repressed polycomb target genes and interact with polycomb repressive complex-2. Molecular Cell, 38, 675–688.PubMedCrossRefGoogle Scholar
  37. Kapranov, P., St Laurent, G., Raz, T., Ozsolak, F., Reynolds, C. P., Sorensen, P. H. et al. (2010). The majority of total nuclear-encoded non-ribosomal RNA in a human cell is ‘dark matter’ un-annotated RNA. BMC Biology 8, 149.Google Scholar
  38. Khalil, A. M., & Driscoll, D. J. (2007). Trimethylation of histone H3 lysine 4 is an epigenetic mark at regions escaping mammalian X inactivation. Epigenetics: official journal of the DNA Methylation Society, 2, 114–118.CrossRefGoogle Scholar
  39. Khalil, A. M., Guttman, M., Huarte, M., Garber, M., Raj, A., Rivea Morales, D., et al. (2009). Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proceedings of the National Academy of Sciences USA, 106, 11667–11672.CrossRefGoogle Scholar
  40. Khalil, A. M., & Rinn, J. L. (2011). RNA-protein interactions in human health and disease. Seminars in Cell & Developmental Biology, 22, 359–365.CrossRefGoogle Scholar
  41. Kim, T. K., Hemberg, M., Gray, J. M., Costa, A. M., Bear, D. M., Wu, J., et al. (2010). Widespread transcription at neuronal activity-regulated enhancers. Nature, 465, 182–187.PubMedCrossRefGoogle Scholar
  42. Kmita, M., & Duboule, D. (2003). Organizing axes in time and space; 25 years of colinear tinkering. Science, 301, 331–333.PubMedCrossRefGoogle Scholar
  43. Kodzius, R., Kojima, M., Nishiyori, H., Nakamura, M., Fukuda, S., Tagami, M., et al. (2006). CAGE: Cap analysis of gene expression. Nature Methods, 3, 211–222.PubMedCrossRefGoogle Scholar
  44. Koziol, M. J., & Rinn, J. L. (2010). RNA traffic control of chromatin complexes. Current Opinion in Genetics & Development, 20, 142–148.CrossRefGoogle Scholar
  45. Lee, J. T., & Bartolomei, M. S. (2013). X-Inactivation, imprinting, and long noncoding RNAs in health and disease. Cell, 152, 1308–1323.PubMedCrossRefGoogle Scholar
  46. Lee, J. T., Davidow, L. S., & Warshawsky, D. (1999). Tsix, a gene antisense to Xist at the X-inactivation centre. Nature Genetics, 21, 400–404.PubMedCrossRefGoogle Scholar
  47. Lemons, D., & McGinnis, W. (2006). Genomic evolution of Hox gene clusters. Science, 313, 1918–1922.PubMedCrossRefGoogle Scholar
  48. Loewer, S., Cabili, M. N., Guttman, M., Loh, Y. H., Thomas, K., Park, I. H., et al. (2010). Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nature Genetics, 42, 1113–1117.PubMedCrossRefGoogle Scholar
  49. Luger, K., Mader, A. W., Richmond, R. K., Sargent, D. F., & Richmond, T. J. (1997). Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature, 389, 251–260.PubMedCrossRefGoogle Scholar
  50. Mallo, M., Wellik, D. M., & Deschamps, J. (2010). Hox genes and regional patterning of the vertebrate body plan. Dev Biol, 344, 7–15.PubMedCrossRefGoogle Scholar
  51. Mercer, T. R., Dinger, M. E., & Mattick, J. S. (2009). Long non-coding RNAs: Insights into functions. Nature Reviews Genetics, 10, 155–159.PubMedCrossRefGoogle Scholar
  52. Mercer, T. R., Gerhardt, D. J., Dinger, M. E., Crawford, J., Trapnell, C., Jeddeloh, J. A., et al. (2012). Targeted RNA sequencing reveals the deep complexity of the human transcriptome. Nature Biotechnology, 30, 99–104.CrossRefGoogle Scholar
  53. Mohammad, F., Mondal, T., Guseva, N., Pandey, G. K., & Kanduri, C. (2010). Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt1. Development, 137, 2493–2499.PubMedCrossRefGoogle Scholar
  54. Moran, V. A., Perera, R. J., & Khalil, A. M. (2012). Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs. Nucleic Acids Research 40, 6391–6400.Google Scholar
  55. Nagano, T., Mitchell, J. A., Sanz, L. A., Pauler, F. M., Ferguson-Smith, A. C., Feil, R., et al. (2008). The air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science, 322, 1717–1720.PubMedCrossRefGoogle Scholar
  56. Ng, P., Wei, C. L., Sung, W. K., Chiu, K. P., Lipovich, L., Ang, C. C., et al. (2005). Gene identification signature (GIS) analysis for transcriptome characterization and genome annotation. Nature Methods, 2, 105–111.PubMedCrossRefGoogle Scholar
  57. Noma, K., Allis, C. D., & Grewal, S. I. (2001). Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science, 293, 1150–1155.PubMedCrossRefGoogle Scholar
  58. Okazaki, Y., Furuno, M., Kasukawa, T., Adachi, J., Bono, H., Kondo, S., et al. (2002). Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature, 420, 563–573.PubMedCrossRefGoogle Scholar
  59. Ota, T., Suzuki, Y., Nishikawa, T., Otsuki, T., Sugiyama, T., Irie, R., et al. (2004). Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature Genetics, 36, 40–45.PubMedCrossRefGoogle Scholar
  60. Pandey, R. R., Mondal, T., Mohammad, F., Enroth, S., Redrup, L., Komorowski, J., et al. (2008). Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Molecular Cell, 32, 232–246.PubMedCrossRefGoogle Scholar
  61. Ponting, C. P., Oliver, P. L., & Reik, W. (2009). Evolution and functions of long noncoding RNAs. Cell, 136, 629–641.PubMedCrossRefGoogle Scholar
  62. Qureshi, I. A., Mattick, J. S., & Mehler, M. F. (2010). Long non-coding RNAs in nervous system function and disease. Brain Research, 1338, 20–35.PubMedCrossRefGoogle Scholar
  63. Rada-Iglesias, A., Bajpai, R., Swigut, T., Brugmann, S. A., Flynn, R. A., & Wysocka, J. (2011). A unique chromatin signature uncovers early developmental enhancers in humans. Nature, 470, 279–283.PubMedCrossRefGoogle Scholar
  64. Rinn, J. L., Euskirchen, G., Bertone, P., Martone, R., Luscombe, N. M., Hartman, S., et al. (2003). The transcriptional activity of human chromosome 22. Genes & Development, 17, 529–540.CrossRefGoogle Scholar
  65. Rinn, J. L., Kertesz, M., Wang, J. K., Squazzo, S. L., Xu, X., Brugmann, S. A., et al. (2007). Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell, 129, 1311–1323.PubMedCrossRefGoogle Scholar
  66. Sado, T., Hoki, Y., & Sasaki, H. (2005). Tsix silences Xist through modification of chromatin structure. Developmental Cell, 9, 159–165.PubMedCrossRefGoogle Scholar
  67. Schmitz, K. M., Mayer, C., Postepska, A., & Grummt, I. (2010). Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. Genes & Development, 24, 2264–2269.CrossRefGoogle Scholar
  68. Schorderet, P., & Duboule, D. (2011). Structural and functional differences in the long non-coding RNA hotair in mouse and human. PLoS Genetics, 7, e1002071.PubMedCrossRefGoogle Scholar
  69. Schwartz, Y. B., & Pirrotta, V. (2007). Polycomb silencing mechanisms and the management of genomic programmes. Nature Reviews Genetics, 8, 9–22.PubMedCrossRefGoogle Scholar
  70. Sessa, L., Breiling, A., Lavorgna, G., Silvestri, L., Casari, G., & Orlando, V. (2007). Noncoding RNA synthesis and loss of Polycomb group repression accompanies the colinear activation of the human HOXA cluster. RNA, 13, 223–239.PubMedCrossRefGoogle Scholar
  71. Sigova, A. A., Mullen, A. C., Molinie, B., Gupta, S., Orlando, D. A., Guenther, M. G., et al. (2013). Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells. Proceedings of the National Academy of Sciences USA, 110, 2876–2881.CrossRefGoogle Scholar
  72. Sleutels, F., Zwart, R., & Barlow, D. P. (2002). The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature, 415, 810–813.PubMedCrossRefGoogle Scholar
  73. Song, L., Zhang, Z., Grasfeder, L. L., Boyle, A. P., Giresi, P. G., Lee, B. K., et al. (2011). Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity. Genome Research, 21, 1757–1767.PubMedCrossRefGoogle Scholar
  74. Sun, B. K., Deaton, A. M., & Lee, J. T. (2006). A transient heterochromatic state in Xist preempts X inactivation choice without RNA stabilization. Molecular Cell, 21, 617–628.PubMedCrossRefGoogle Scholar
  75. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126, 663–676.PubMedCrossRefGoogle Scholar
  76. Trapnell, C., Williams, B. A., Pertea, G., Mortazavi, A., Kwan, G., van Baren, M. J., et al. (2010). Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nature Biotechnology, 28, 511–515.PubMedCrossRefGoogle Scholar
  77. Tsai, M. C., Manor, O., Wan, Y., Mosammaparast, N., Wang, J. K., Lan, F., et al. (2010). Long noncoding RNA as modular scaffold of histone modification complexes. Science, 329, 689–693.PubMedCrossRefGoogle Scholar
  78. Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., et al. (2001). The sequence of the human genome. Science, 291, 1304–1351.PubMedCrossRefGoogle Scholar
  79. Wang, K. C., & Chang, H. Y. (2011). Molecular mechanisms of long noncoding RNAs. Molecular Cell, 43, 904–914.PubMedCrossRefGoogle Scholar
  80. Wang, K. C., Yang, Y. W., Liu, B., Sanyal, A., Corces-Zimmerman, R., Chen, Y., et al. (2011). A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature, 472, 120–124.PubMedCrossRefGoogle Scholar
  81. Wang, Z., Zang, C., Rosenfeld, J. A., Schones, D. E., Barski, A., Cuddapah, S., et al. (2008). Combinatorial patterns of histone acetylations and methylations in the human genome. Nature Genetics, 40, 897–903.PubMedCrossRefGoogle Scholar
  82. Werner, A., Carlile, M., & Swan, D. (2009). What do natural antisense transcripts regulate? RNA biology 6, 43–48. Google Scholar
  83. Yap, K. L., Li, S., Munoz-Cabello, A. M., Raguz, S., Zeng, L., Mujtaba, S., et al. (2010). Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Molecular Cell, 38, 662–674.PubMedCrossRefGoogle Scholar
  84. Yildirim, E., Kirby, J. E., Brown, D. E., Mercier, F. E., Sadreyev, R. I., Scadden, D. T., et al. (2013). Xist RNA is a potent suppressor of hematologic cancer in mice. Cell, 152, 727–742.PubMedCrossRefGoogle Scholar
  85. Zentner, G. E., Tesar, P. J., & Scacheri, P. C. (2011). Epigenetic signatures distinguish multiple classes of enhancers with distinct cellular functions. Genome Research, 21, 1273–1283.PubMedCrossRefGoogle Scholar
  86. Zhao, J., Ohsumi, T. K., Kung, J. T., Ogawa, Y., Grau, D. J., Sarma, K., et al. (2010). Genome-wide identification of polycomb-associated RNAs by RIP-seq. Molecular Cell, 40, 939–953.PubMedCrossRefGoogle Scholar
  87. Zhao, J., Sun, B. K., Erwin, J. A., Song, J. J., & Lee, J. T. (2008). Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 322, 750–756.Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Daniel C. Factor
    • 1
  • Paul J. Tesar
    • 1
  • Ahmad M. Khalil
    • 1
  1. 1.Department of Genetics and Genome SciencesCase Western Reserve University School of MedicineClevelandUSA

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