The advent of next generation sequencing revealed that a fraction of transcribed RNAs (short and long RNAs) is non-coding. Long non-coding RNAs (lncRNAs) have a crucial role in regulating gene expression and in epigenetics (chromatin and histones remodeling). LncRNAs may have different roles: gene activators (signaling), repressors (decoy), cis and trans gene expression regulators (guides) and chromatin modificators (scaffolds) without the need to be mutually exclusive. LncRNAs are also implicated in a number of diseases. The huge amount of inhomogeneous data produced so far poses several bioinformatics challenges spanning from the simple annotation to the more complex functional annotation. In this review, we report and discuss several bioinformatics resources freely available and dealing with the study of lncRNAs. To our knowledge, this is the first review summarizing all the available bioinformatics resources on lncRNAs appeared in the literature after the completion of the human genome project. Therefore, the aim of this review is to provide a little guide for biologists and bioinformaticians looking for dedicated resources, public repositories and other tools for lncRNAs functional analysis.
References
[1]
ENCODE Project Consortium. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 2004, 306, 636–640.
[2]
ENCODE Project Consortium. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007, 447, 799–816.
[3]
Mattick, J.S. The genetic signatures of noncoding RNAs. PLoS Genet 2009, 5, e1000459.
[4]
Mattick, J.S. The functional genomics of noncoding RNA. Science 2005, 309, 1527–1528.
Mercer, T.R.; Dinger, M.E.; Mattick, J.S. Long non-coding RNAs: Insights into functions. Nat. Rev. Genet 2009, 10, 155–159.
[7]
Nagano, T.; Fraser, P. No-nonsense functions for long noncoding RNAs. Cell 2011, 145, 178–181.
[8]
Wilusz, J.E.; Sunwoo, H.; Spector, D.L. Long noncoding RNAs: Functional surprises from the RNA world. Genes Dev 2009, 23, 1494–1504.
[9]
Ponting, C.P.; Oliver, P.L.; Reik, W. Evolution and functions of long noncoding RNAs. Cell 2009, 136, 629–641.
[10]
Kim, T.K.; Hemberg, M.; Gray, J.M.; Costa, A.M.; Bear, D.M.; Wu, J.; Harmin, D.A.; Laptewicz, M.; Barbara-Haley, K.; Kuersten, S.; et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 2010, 465, 182–187.
[11]
De Santa, F.; Barozzi, I.; Mietton, F.; Ghisletti, S.; Polletti, S.; Tusi, B.K.; Muller, H.; Ragoussis, J.; Wei, C.L.; Natoli, G. A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biol 2010, 8, e1000384.
[12]
Orom, U.A.; Derrien, T.; Beringer, M.; Gumireddy, K.; Gardini, A.; Bussotti, G.; Lai, F.; Zytnicki, M.; Notredame, C.; Huang, Q.; et al. Long noncoding RNAs with enhancer-like function in human cells. Cell 2010, 143, 46–58.
[13]
Amaral, P.P.; Clark, M.B.; Gascoigne, D.K.; Dinger, M.E.; Mattick, J.S. lncRNAdb: A reference database for long noncoding RNAs. Nucleic Acids Res 2011, 39, D146–D151.
[14]
Baker, M. Long noncoding RNAs: the search for function. Nat. Meth 2011, 8, 379–383.
[15]
He, S.; Su, H.; Liu, C.; Skogerbo, G.; He, H.; He, D.; Zhu, X.; Liu, T.; Zhao, Y.; Chen, R. MicroRNA-encoding long non-coding RNAs. BMC Genomics 2008, 9, 236.
[16]
Kanduri, C.; Whitehead, J.; Mohammad, F. The long and the short of it: RNA-directed chromatin asymmetry in mammalian X-chromosome inactivation. FEBS Lett 2009, 583, 857–864.
[17]
Lee, J.T. Lessons from X-chromosome inactivation: long ncRNA as guides and tethers to the epigenome. Genes Dev 2009, 23, 1831–1842.
[18]
Mohammad, F.; Mondal, T.; Kanduri, C. Epigenetics of imprinted long noncoding RNAs. Epigenetics 2009, 4, 277–286.
[19]
Clemson, C.M.; Hutchinson, J.N.; Sara, S.A.; Ensminger, A.W.; Fox, A.H.; Chess, A.; Lawrence, J.B. An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. Mol. Cell 2009, 33, 717–726.
[20]
Sasaki, Y.T.; Ideue, T.; Sano, M.; Mituyama, T.; Hirose, T. MENepsilon/beta noncoding RNAs are essential for structural integrity of nuclear paraspeckles. Proc. Natl. Acad. Sci. USA 2009, 106, 2525–2530.
[21]
Schoeftner, S.; Blasco, M.A. A “higher order” of telomere regulation: Telomere heterochromatin and telomeric RNAs. EMBO J 2009, 28, 2323–2336.
[22]
Wong, L.H.; Brettingham-Moore, K.H.; Chan, L.; Quach, J.M.; Anderson, M.A.; Northrop, E.L.; Hannan, R.; Saffery, R.; Shaw, M.L.; Williams, E.; et al. Centromere RNA is a key component for the assembly of nucleoproteins at the nucleolus and centromere. Genome Res 2007, 17, 1146–1160.
[23]
Ferri, F.; Bouzinba-Segard, H.; Velasco, G.; Hube, F.; Francastel, C. Non-coding murine centromeric transcripts associate with and potentiate Aurora B kinase. Nucleic Acids Res 2009, 37, 5071–5080.
[24]
Willingham, A.T.; Orth, A.P.; Batalov, S.; Peters, E.C.; Wen, B.G.; Aza-Blanc, P.; Hogenesch, J.B.; Schultz, P.G. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 2005, 309, 1570–1573.
[25]
Khalil, A.M.; Guttman, M.; Huarte, M.; Garber, M.; Raj, A.; Rivea Morales, D.; Thomas, K.; Presser, A.; Bernstein, B.E.; van Oudenaarden, A.; et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl. Acad. Sci. USA 2009, 106, 11667–11672.
[26]
Guttman, M.; Amit, I.; Garber, M.; French, C.; Lin, M.F.; Feldser, D.; Huarte, M.; Zuk, O.; Carey, B.W.; Cassady, J.P.; et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 2009, 458, 223–227.
[27]
Huarte, M.; Rinn, J.L. Large non-coding RNAs: Missing links in cancer? Hum. Mol. Genet 2010, 19, R152–R161.
[28]
Zong, X.; Tripathi, V.; Prasanth, K.V. RNA splicing control: Yet another gene regulatory role for long nuclear noncoding RNAs. RNA Biol 2011, 8, 968–977.
[29]
Kapranov, P.; Cheng, J.; Dike, S.; Nix, D.A.; Duttagupta, R.; Willingham, A.T.; Stadler, P.F.; Hertel, J.; Hackermüller, J.; Hofacker, I.L.; et al. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 2007, 316, 1484–1488.
[30]
Wu, Q.; Kim, Y.C.; Lu, J.; Xuan, Z.; Chen, J.; Zheng, Y.; Zhou, T.; Zhang, M.Q.; Wu, C.I.; Wang, S.M. Poly A-transcripts expressed in HeLa cells. PLoS One 2008, 3, e2803.
[31]
Martone, R.; Euskirchen, G.; Bertone, P.; Hartman, S.; Royce, T.E.; Luscombe, N.M.; Rinn, J.L.; Nelson, F.K.; Miller, P.; Gerstein, M.; et al. Distribution of NF-kappaB-binding sites across human chromosome 22. Proc. Natl. Acad. Sci. USA 2003, 100, 12247–12252.
[32]
Prasanth, K.V.; Spector, D.L. Eukaryotic regulatory RNAs: An answer to the “genome complexity” conundrum. Genes Dev 2007, 21, 11–42.
[33]
Dieci, G.; Fiorino, G.; Castelnuovo, M.; Teichmann, M.; Pagano, A. The expanding RNA polymerase III transcriptome. Trends Genet 2007, 23, 614–622.
Wang, K.C.; Chang, H.Y. Molecular mechanisms of long noncoding RNAs. Mol. Cell 2011, 43, 904–914.
[36]
Nagano, T.; Mitchell, J.A.; Sanz, L.A.; Pauler, F.M.; Ferguson-Smith, A.C.; Feil, R.; Fraser, P. The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 2008, 322, 1717–1720.
[37]
Pontier, D.B.; Gribnau, J. Xist regulation and function explored. Hum. Genet 2011, 130, 223–236.
[38]
Gontan, C.; Jonkers, I.; Gribnau, J. Long noncoding RNAs and X chromosome inactivation. Prog. Mol. Subcell. Biol 2011, 51, 43–64.
[39]
Huarte, M.; Guttman, M.; Feldser, D.; Garber, M.; Koziol, M.J.; Kenzelmann-Broz, D.; Khalil, A.M.; Zuk, O.; Amit, I.; Rabani, M.; et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 2010, 142, 409–419.
[40]
Hung, T.; Wang, Y.; Lin, M.F.; Koegel, A.K.; Kotake, Y.; Grant, G.D.; Horlings, H.M.; Shah, N.; Umbricht, C.; Wang, P.; et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat. Genet 2011, 43, 621–629.
[41]
Azzalin, C.M.; Reichenbach, P.; Khoriauli, L.; Giulotto, E.; Lingner, J. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 2007, 318, 798–801.
[42]
Redon, S.; Reichenbach, P.; Lingner, J. The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase. Nucleic Acids Res 2010, 38, 5797–5806.
[43]
Spitale, R.C.; Tsai, M.C.; Chang, H.Y. RNA templating the epigenome: Long noncoding RNAs as molecular scaffolds. Epigenetics 2011, 6, 539–543.
[44]
Collins, K. Physiological assembly and activity of human telomerase complexes. Mech. Ageing Dev 2008, 129, 91–98.
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. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 2007, 129, 1311–1323.
[47]
Szymanski, M.; Erdmann, V.A.; Barciszewski, J. Noncoding regulatory RNAs database. Nucleic Acids Res 2003, 31, 429–431.
[48]
Griffiths-Jones, S.; Bateman, A.; Marshall, M.; Khanna, A.; Eddy, S.R. Rfam: An RNA family database. Nucleic Acids Res 2003, 31, 439–441.
[49]
Gardner, P.P.; Daub, J.; Tate, J.G.; Nawrocki, E.P.; Kolbe, D.L.; Lindgreen, S.; Wilkinson, A.C.; Finn, R.D.; Griffiths-Jones, S.; Eddy, S.R.; et al. Rfam: Updates to the RNA families database. Nucleic Acids Res 2009, 37, D136–D140.
Dinger, M.E.; Pang, K.C.; Mercer, T.R.; Crowe, M.L.; Grimmond, S.M.; Mattick, J.S. NRED: A database of long noncoding RNA expression. Nucleic Acids Res 2009, 37, D122–D126.
[61]
Cabili, M.N.; Trapnell, C.; Goff, L.; Koziol, M.; Tazon-Vega, B.; Regev, A.; Rinn, J.L. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev 2011, 25, 1915–1927.
[62]
Risueno, A.; Fontanillo, C.; Dinger, M.E.; De Las Rivas, J. GATExplorer: Genomic and transcriptomic explorer; mapping expression probes to gene loci, transcripts, exons and ncRNAs. BMC Bioinforma 2010, 11, 221.
[63]
Liao, Q.; Xiao, H.; Bu, D.; Xie, C.; Miao, R.; Luo, H.; Zhao, G.; Yu, K.; Zhao, H.; Skogerbo, G.; et al. ncFANs: A web server for functional annotation of long non-coding RNAs. Nucleic Acids Res 2011, 39, W118–W124.
[64]
Deng, W.; Zhu, X.; Skogerb?, G.; Zhao, Y.; Fu, Z.; Wang, Y.; He, H.; Cai, L.; Sun, H.; Liu, C.; et al. Organization of the Caenorhabditis elegans small non-coding transcriptome: genomic features, biogenesis, and expression. Genome Res 2006, 16, 20–29.
[65]
Maeda, N.; Kasukawa, T.; Oyama, R.; Gough, J.; Frith, M.; Engstr?m, P.G.; Lenhard, B.; Aturaliya, R.N.; Batalov, S.; Beisel, K.W.; et al. Transcript annotation in FANTOM3: mouse gene catalog based on physical cDNAs. PLoS Genet 2006, 2, e62.
[66]
Griffiths-Jones, S.; Grocock, R.J.; van Dongen, S.; Bateman, A.; Enright, A.J. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 2006, 34, D140–D144.
[67]
Lestrade, L.; Weber, M.J. snoRNA-LBME-db, a comprehensive database of human H/ACA and C/D box snoRNAs. Nucleic Acids Res 2006, 34, D158–D162.
[68]
Barrett, T.; Troup, D.B.; Wilhite, S.E.; Ledoux, P.; Rudnev, D.; Evangelista, C.; Kim, I.F.; Soboleva, A.; Tomashevsky, M.; Edgar, R. NCBI GEO: mining tens of millions of expression profiles—database and tools update. Nucleic Acids Res 2007, 35, D760–D765.
[69]
Royo, H.; Cavaille, J. Non-coding RNAs in imprinted gene clusters. Biol. Cell 2008, 100, 149–166.
[70]
Sahoo, T.; del Gaudio, D.; German, J.R.; Shinawi, M.; Peters, S.U.; Person, R.E.; Garnica, A.; Cheung, S.W.; Beaudet, A.L. Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat. Genet 2008, 40, 719–721.
[71]
Bliek, J.; Terhal, P.; van den Bogaard, M.J.; Maas, S.; Hamel, B.; Salieb-Beugelaar, G.; Simon, M.; Letteboer, T.; van der Smagt, J.; Kroes, H.; Mannens, M. Hypomethylation of the H19 gene causes not only Silver-Russell syndrome (SRS) but also isolated asymmetry or an SRS-like phenotype. Am. J. Hum. Genet 2006, 78, 604–614.
[72]
Zhang, X.; Zhou, Y.; Mehta, K.R.; Danila, D.C.; Scolavino, S.; Johnson, S.R.; Klibanski, A. A pituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells. J. Clin. Endocrinol. Metab 2003, 88, 5119–5126.
[73]
Koerner, M.V.; Pauler, F.M.; Huang, R.; Barlow, D.P. The function of non-coding RNAs in genomic imprinting. Development 2009, 136, 1771–1783.
[74]
Liao, Q.; Liu, C.; Yuan, X.; Kang, S.; Miao, R.; Xiao, H.; Zhao, G.; Luo, H.; Bu, D.; Zhao, H.; et al. Large-scale prediction of long non-coding RNA functions in a coding-non-coding gene co-expression network. Nucleic Acids Res 2011, 39, 3864–3878.
[75]
Carninci, P.; Kasukawa, T.; Katayama, S.; Gough, J.; Frith, M.C.; Maeda, N.; Oyama, R.; Ravasi, T.; Lenhard, B.; Wells, C.; et al. The transcriptional landscape of the mammalian genome. Science 2005, 309, 1559–1563.
[76]
Mikkelsen, T.S.; Ku, M.; Jaffe, D.B.; Issac, B.; Lieberman, E.; Giannoukos, G.; Alvarez, P.; Brockman, W.; Kim, T.-K.; Koche, R.P.; et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 2007, 448, 553–560.
[77]
Garmire, L.X.; Garmire, D.G.; Huang, W.; Yao, J.; Glass, C.K.; Subramaniam, S. A global clustering algorithm to identify long intergenic non-coding RNA—with applications in mouse macrophages. PLoS One 2011, 6, e24051.
Kanhere, A.; Viiri, K.; Araujo, C.C.; Rasaiyaah, J.; Bouwman, R.D.; Whyte, W.A.; Pereira, C.F.; Brookes, E.; Walker, K.; Bell, G.W.; et al. Short RNAs are transcribed from repressed polycomb target genes and interact with polycomb repressive complex-2. Mol. Cell 2010, 38, 675–688.
[81]
Zhao, J.; Sun, B.K.; Erwin, J.A.; Song, J.J.; Lee, J.T. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 2008, 322, 750–756.