It is clear that RNA has a diverse set of functions and is more than just a messenger between gene and protein. The mammalian genome is extensively transcribed, giving rise to thousands of non-coding transcripts. Whether all of these transcripts are functional is debated, but it is evident that there are many functional large non-coding RNAs (ncRNAs). Recent studies have begun to explore the functional diversity and mechanistic role of these large ncRNAs. Here we synthesize these studies to provide an emerging model whereby large ncRNAs might achieve regulatory specificity through modularity, assembling diverse combinations of proteins and possibly RNA and DNA interactions.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Necroptosis-Related LncRNA Signatures for Prognostic Prediction in Uterine Corpora Endometrial Cancer
Reproductive Sciences Open Access 19 July 2022
LncRNA LYPLAL1-AS1 rejuvenates human adipose-derived mesenchymal stem cell senescence via transcriptional MIRLET7B inactivation
Cell & Bioscience Open Access 21 April 2022
Predict the role of lncRNA in kidney aging based on RNA sequencing
BMC Genomics Open Access 02 April 2022
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Warner, J. R., Soeiro, R., Birnboim, H. C., Girard, M. & Darnell, J. E. Rapidly labeled HeLa cell nuclear RNA. I. Identification by zone sedimentation of a heterogeneous fraction separate from ribosomal precursor RNA. J. Mol. Biol. 19, 349–361 (1966).
Salditt-Georgieff, M., Harpold, M. M., Wilson, M. C. & Darnell, J. E., Jr. Large heterogeneous nuclear ribonucleic acid has three times as many 5′ caps as polyadenylic acid segments, and most caps do not enter polyribosomes. Mol. Cell. Biol. 1, 179–187 (1981). This paper demonstrates an abundant class of RNA species that do not enter polyribosomes.
Weinberg, R. A. & Penman, S. Small molecular weight monodisperse nuclear RNA. J. Mol. Biol. 38, 289–304 (1968).
Zieve, G. & Penman, S. Small RNA species of the HeLa cell: metabolism and subcellular localization. Cell 8, 19–31 (1976).
Gesteland, R. F., Cech, T. & Atkins, J. F. The RNA World : The Nature of Modern RNA Suggests a Prebiotic RNA World. 3rd edn (Cold Spring Harbor Laboratory Press, 2006).
Eddy, S. R. Non-coding RNA genes and the modern RNA world. Nature Rev. Genet. 2, 919–929 (2001).
Pachnis, V., Brannan, C. I. & Tilghman, S. M. The structure and expression of a novel gene activated in early mouse embryogenesis. EMBO J. 7, 673–681 (1988).
Brannan, C. I., Dees, E. C., Ingram, R. S. & Tilghman, S. M. The product of the H19 gene may function as an RNA. Mol. Cell. Biol. 10, 28–36 (1990). This paper was the first report of a large ncRNA showing that the H19 transcript lacked conserved ORFs and did not make a protein product in vivo.
Brown, C. J. et al. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349, 38–44 (1991).
Penny, G. D., Kay, G. F., Sheardown, S. A., Rastan, S. & Brockdorff, N. Requirement for Xist in X chromosome inactivation. Nature 379, 131–137 (1996).
Sleutels, F., Zwart, R. & Barlow, D. P. The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature 415, 810–813 (2002).
Young, T. L., Matsuda, T. & Cepko, C. L. The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina. Curr. Biol. 15, 501–512 (2005).
Willingham, A. T. et al. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 309, 1570–1573 (2005).
Rinn, J. L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).
Carninci, P. et al. The transcriptional landscape of the mammalian genome. Science 309, 1559–1563 (2005). This paper describes the large-scale cDNA sequencing efforts in the mouse genome and reveals many thousands of non-coding transcripts.
Birney, E. et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799–816 (2007).
Bertone, P. et al. Global identification of human transcribed sequences with genome tiling arrays. Science 306, 2242–2246 (2004).
Kapranov, P. et al. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316, 1484–1488 (2007).
Rinn, J. L. et al. The transcriptional activity of human Chromosome 22. Genes Dev. 17, 529–540 (2003).
Kapranov, P. et al. Large-scale transcriptional activity in chromosomes 21 and 22. Science 296, 916–919 (2002).
Ebisuya, M., Yamamoto, T., Nakajima, M. & Nishida, E. Ripples from neighbouring transcription. Nature Cell Biol. 10, 1106–1113 (2008).
Struhl, K. Transcriptional noise and the fidelity of initiation by RNA polymerase II. Nature Struct. Mol. Biol. 14, 103–105 (2007).
Guttman, M. et al. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477, 295–300 (2011).
Orom, U. A. et al. Long noncoding RNAs with enhancer-like function in human cells. Cell 143, 46–58 (2010).
Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223–227 (2009). This paper applied a chromatin signature to identify lincRNAs and used a guilt-by-association approach to classify their likely functions in diverse biological processes.
Huarte, M. et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142, 409–419 (2010).
Hung, T. et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nature Genet. 43, 621–629 (2011).
Wang, K. C. et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472, 120–124 (2011).
Wilusz, J. E., Freier, S. M. & Spector, D. L. 3′ end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell 135, 919–932 (2008).
Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nature Methods 5, 621–628 (2008).
Guttman, M. et al. Ab initio reconstruction of cell type-specific transcriptomes in mouse reveals the conserved multi-exonic structure of lincRNAs. Nature Biotechnol. 28, 503–510 (2010).
Cabili, M. N. et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 25, 1915–1927 (2011).
Mercer, T. R., Dinger, M. E., Sunkin, S. M., Mehler, M. F. & Mattick, J. S. Specific expression of long noncoding RNAs in the mouse brain. Proc. Natl Acad. Sci. USA 105, 716–721 (2008).
De Santa, F. et al. A large fraction of extragenic RNA Pol II transcription sites overlap enhancers. PLoS Biol. 8, e1000384 (2010).
Kim, T. K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187 (2010).
Ravasi, T. et al. Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome. Genome Res. 16, 11–19 (2006).
Ponjavic, J., Ponting, C. P. & Lunter, G. Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs. Genome Res. 17, 556–565 (2007).
Taft, R. J. et al. Tiny RNAs associated with transcription start sites in animals. Nature Genet. 41, 572–578 (2009).
Seila, A. C. et al. Divergent transcription from active promoters. Science 322, 1849–1851 (2008).
Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).
Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).
Visel, A. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009).
Heintzman, N. D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009).
Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).
Khalil, A. M. et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl Acad. Sci. USA 106, 11667–11672 (2009).
Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49 (2011).
Loewer, S. et al. Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nature Genet. 42, 1113–1117 (2010).
Dinger, M. E., Pang, K. C., Mercer, T. R. & Mattick, J. S. Differentiating protein-coding and noncoding RNA: challenges and ambiguities. PLoS Comput. Biol. 4, e1000176 (2008).
Brockdorff, N. et al. 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 (1992).
Lin, M. F., Deoras, A. N., Rasmussen, M. D. & Kellis, M. Performance and scalability of discriminative metrics for comparative gene identification in 12 Drosophila genomes. PLoS Comput. Biol. 4, e1000067 (2008).
Lin, M. F., Jungreis, I. & Kellis, M. PhyloCSF: a comparative genomics method to distinguish protein coding and non-coding regions. Bioinformatics 27, i275–i282 (2011).
Finn, R. D. et al. The Pfam protein families database. Nucleic Acids Res. 38, D211–D222 (2010).
Ingolia, N. T., Lareau, L. F. & Weissman, J. S. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147, 789–802 (2011).
Galindo, M. I., Pueyo, J. I., Fouix, S., Bishop, S. A. & Couso, J. P. Peptides encoded by short ORFs control development and define a new eukaryotic gene family. PLoS Biol. 5, e106 (2007). This paper demonstrates the existence of functional small peptides within a presumed 'non-coding' transcript through ORF conservation, in vivo protein identification and functional analysis.
Kondo, T. et al. Small peptides switch the transcriptional activity of Shavenbaby during Drosophila embryogenesis. Science 329, 336–339 (2010).
Jiao, Y. & Meyerowitz, E. M. Cell-type specific analysis of translating RNAs in developing flowers reveals new levels of control. Mol. Syst. Biol. 6, 419 (2010).
Li, Y. M. et al. The H19 transcript is associated with polysomes and may regulate IGF2 expression in trans. J. Biol. Chem. 273, 28247–28252 (1998).
Cai, X. & Cullen, B. R. The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA 13, 313–316 (2007).
Yang, L. et al. ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell 147, 773–788 (2011).
Clamp, M. et al. Distinguishing protein-coding and noncoding genes in the human genome. Proc. Natl Acad. Sci. USA 104, 19428–19433 (2007).
Kastenmayer, J. P. et al. Functional genomics of genes with small open reading frames (sORFs) in S. cerevisiae. Genome Res. 16, 365–373 (2006).
Hanada, K., Zhang, X., Borevitz, J. O., Li, W. H. & Shiu, S. H. A large number of novel coding small open reading frames in the intergenic regions of the Arabidopsis thaliana genome are transcribed and/or under purifying selection. Genome Res 17, 632–640 (2007).
Mattick, J. S. The genetic signatures of noncoding RNAs. PLoS Genet. 5, e1000459 (2009).
Tsai, M. C. et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693 (2010). This paper identified multiple protein-interaction domains within HOTAIR that together allowed it to carry out its function, which demonstrated that a large ncRNA can act as a molecular scaffold.
Gupta, R. A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010).
Zappulla, D. C. & Cech, T. R. Yeast telomerase RNA: a flexible scaffold for protein subunits. Proc. Natl Acad. Sci. USA 101, 10024–10029 (2004). This paper demonstrated that telomerase RNA can bridge proteins by showing that protein interaction domains can be swapped and spacer regions deleted with minimal impact on the function of the RNA.
Korostelev, A. & Noller, H. F. The ribosome in focus: new structures bring new insights. Trends Biochem. Sci. 32, 434–441 (2007).
Ivanova, N. et al. Dissecting self-renewal in stem cells with RNA interference. Nature 442, 533–538 (2006).
Martens, J. A., Laprade, L. & Winston, F. Intergenic transcription is required to repress the Saccharomyces cerevisiae SER3 gene. Nature 429, 571–574 (2004).
Schmitt, S., Prestel, M. & Paro, R. Intergenic transcription through a Polycomb group response element counteracts silencing. Genes Dev. 19, 697–708 (2005).
Lee, J. T. Lessons from X-chromosome inactivation: long ncRNA as guides and tethers to the epigenome. Genes Dev. 23, 1831–1842 (2009).
Ponjavic, J., Oliver, P. L., Lunter, G. & Ponting, C. P. Genomic and transcriptional co-localization of protein-coding and long non-coding RNA pairs in the developing brain. PLoS Genet. 5, e1000617 (2009).
Tian, D., Sun, S. & Lee, J. T. The long noncoding RNA, Jpx, is a molecular switch for X chromosome inactivation. Cell 143, 390–403 (2010).
Koerner, M. V., Pauler, F. M., Huang, R. & Barlow, D. P. The function of non-coding RNAs in genomic imprinting. Development 136, 1771–1783 (2009).
Pandey, R. R. et al. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol. Cell 32, 232–246 (2008).
Bertani, S., Sauer, S., Bolotin, E. & Sauer, F. The noncoding RNA Mistral activates Hoxa6 and Hoxa7 expression and stem cell differentiation by recruiting MLL1 to chromatin. Mol. Cell 43, 1040–1046 (2011).
Feng, J. et al. The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes Dev. 20, 1470–1484 (2006).
Koziol, M. J. & Rinn, J. L. RNA traffic control of chromatin complexes. Curr. Opin. Genet. Dev. 20, 142–148 (2010).
Maison, C. et al. Higher-order structure in pericentric heterochromatin involves a distinct pattern of histone modification and an RNA component. Nature Genet. 30, 329–334 (2002).
Bernstein, E. et al. Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Mol. Cell. Biol. 26, 2560–2569 (2006).
Wutz, A., Rasmussen, T. P. & Jaenisch, R. Chromosomal silencing and localization are mediated by different domains of Xist RNA. Nature Genet. 30, 167–174 (2002). This paper reported the generation of deletion mutants across the Xist locus and identified the discrete domains responsible for the silencing and localization roles of the RNA.
Chu, C., Qu, K., Zhong, F. L., Artandi, S. E. & Chang, H. Y. Genomic maps of long noncoding RNA occupancy reveal principles of RNA–chromatin interactions. Mol. Cell 44, 667–678 (2011).
Simon, M. D. et al. The genomic binding-sites of a non-coding RNA. Proc. Natl Acad. Sci. USA 108, 20497–20502 (2011).
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 322, 750–756 (2008).
Plath, K., Mlynarczyk-Evans, S., Nusinow, D. A. & Panning, B. Xist RNA and the mechanism of X chromosome inactivation. Annu. Rev. Genet. 36, 233–278 (2002).
Nagano, T. et al. The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 322, 1717–1720 (2008).
Zhao, J. et al. Genome-wide identification of Polycomb-associated RNAs by RIP-seq. Mol. Cell 40, 939–953 (2010).
Kaneko, S. et al. Phosphorylation of the PRC2 component Ezh2 is cell cycle-regulated and up-regulates its binding to ncRNA. Genes Dev. 24, 2615–2620 (2010).
Wang, X. et al. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454, 126–130 (2008).
Kino, T., Hurt, D. E., Ichijo, T., Nader, N. & Chrousos, G. P. Noncoding RNA Gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci. Signal 3, ra8 (2010).
Salmena, L., Poliseno, L., Tay, Y., Kats, L. & Pandolfi, P. P. A ceRNA hypothesis: the Rosetta stone of a hidden RNA language? Cell 146, 353–358 (2011).
Cesana, M. et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147, 358–369 (2011).
Greider, C. W. & Blackburn, E. H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43, 405–413 (1985).
Feng, J. et al. The RNA component of human telomerase. Science 269, 1236–1241 (1995).
Lingner, J. et al. Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276, 561–567 (1997).
Jeon, Y. & Lee, J. T. YY1 tethers Xist RNA to the inactive X nucleation center. Cell 146, 119–133 (2011).
Hasegawa, Y., Brockdorff, N., Kawano, S., Tsutui, K. & Nakagawa, S. The matrix protein hnRNP U is required for chromosomal localization of Xist RNA. Dev. Cell 19, 469–476 (2010).
Schmitz, K. M., Mayer, C., Postepska, A. & Grummt, I. Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. Genes Dev. 24, 2264–2269 (2010).
Martianov, I., Ramadass, A., Serra Barros, A., Chow, N. & Akoulitchev, A. Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature 445, 666–670 (2007).
Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).
We thank M. Cabili, J. Engreitz, M. Garber, P. McDonel and A. Pauli for their reading and suggestions; T. Cech for comments and suggestions; E. Lander for helpful discussions and ideas; and S. Knemeyer and L. Gaffney for assistance with figures in this Review.
The authors declare no competing financial interests.
Reprints and permissions information is available at www.nature.com/reprints
Rights and permissions
About this article
Cite this article
Guttman, M., Rinn, J. Modular regulatory principles of large non-coding RNAs. Nature 482, 339–346 (2012). https://doi.org/10.1038/nature10887
This article is cited by
The critical roles of m6A RNA methylation in lung cancer: from mechanism to prognosis and therapy
British Journal of Cancer (2023)
Genomic survey of high-throughput RNA-Seq data implicates involvement of long intergenic non-coding RNAs (lincRNAs) in cytoplasmic male-sterility and fertility restoration in pigeon pea
Genes & Genomics (2023)
Comprehensive investigation of long non-coding RNAs in an endophytic fungus Calcarisporium arbuscula NRRL 3705
Archives of Microbiology (2023)
Necroptosis-Related LncRNA Signatures for Prognostic Prediction in Uterine Corpora Endometrial Cancer
Reproductive Sciences (2023)
LncRNA XIST contributes to epithelial–mesenchymal transformation in posterior opacity via regulating miR-98-5p/COL5A2 axis and PI3K/Akt/FOXO1 pathway
Molecular & Cellular Toxicology (2023)
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.