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Gene regulation by long non-coding RNAs and its biological functions

Nature Reviews Molecular Cell Biology volume 22, pages 96–118 (2021)Cite this article

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An Author Correction to this article was published on 08 January 2021

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Abstract

Evidence accumulated over the past decade shows that long non-coding RNAs (lncRNAs) are widely expressed and have key roles in gene regulation. Recent studies have begun to unravel how the biogenesis of lncRNAs is distinct from that of mRNAs and is linked with their specific subcellular localizations and functions. Depending on their localization and their specific interactions with DNA, RNA and proteins, lncRNAs can modulate chromatin function, regulate the assembly and function of membraneless nuclear bodies, alter the stability and translation of cytoplasmic mRNAs and interfere with signalling pathways. Many of these functions ultimately affect gene expression in diverse biological and physiopathological contexts, such as in neuronal disorders, immune responses and cancer. Tissue-specific and condition-specific expression patterns suggest that lncRNAs are potential biomarkers and provide a rationale to target them clinically. In this Review, we discuss the mechanisms of lncRNA biogenesis, localization and functions in transcriptional, post-transcriptional and other modes of gene regulation, and their potential therapeutic applications.

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Fig. 1: Biogenesis and cellular fates of long non-coding RNAs.
Fig. 2: Chromatin regulation mediated by long non-coding RNAs.
Fig. 3: Transcription regulation by long non-coding RNAs.
Fig. 4: Roles of long non-coding RNAs in nuclear organization.
Fig. 5: Post-transcriptional functions of trans-acting long non-coding RNAs.
Fig. 6: The involvement of long non-coding RNAs in cancer.

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References

  1. Uszczynska-Ratajczak, B., Lagarde, J., Frankish, A., Guigo, R. & Johnson, R. Towards a complete map of the human long non-coding RNA transcriptome. Nat. Rev. Genet. 19, 535–548 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fang, S. et al. NONCODEV5: a comprehensive annotation database for long non-coding RNAs. Nucleic Acids Res. 46, D308–D314 (2018).

    Article  CAS  PubMed  Google Scholar 

  3. Wu, H., Yang, L. & Chen, L. L. The diversity of long noncoding RNAs and their generation. Trends Genet. 33, 540–552 (2017).

    Article  CAS  PubMed  Google Scholar 

  4. Derrien, T. et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 22, 1775–1789 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tian, B. & Manley, J. L. Alternative polyadenylation of mRNA precursors. Nat. Rev. Mol. Cell Biol. 18, 18–30 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Guo, C. J. et al. Distinct processing of lncRNAs contributes to non-conserved functions in stem cells. Cell 181, 621–636.e22 (2020). This paper shows that conserved lncRNAs exhibit distinct subcellular localization and function in human compared with mouse pluripotent cells and that the relatively high evolutionary plasticity of lncRNAs can support species-specific gene expression programmes.

    Article  CAS  PubMed  Google Scholar 

  7. Quinn, J. J. et al. Rapid evolutionary turnover underlies conserved lncRNA–genome interactions. Genes Dev. 30, 191–207 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hezroni, H. et al. Principles of long noncoding RNA evolution derived from direct comparison of transcriptomes in 17 species. Cell Rep. 11, 1110–1122 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lagarde, J. et al. High-throughput annotation of full-length long noncoding RNAs with capture long-read sequencing. Nat. Genet. 49, 1731–1740 (2017). This paper re-annotates GENCODE lncRNAs by developing RNA capture long seq for full-length lncRNAs, which provides a comprehensive lncRNA annotation resource.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mele, M. et al. Chromatin environment, transcriptional regulation, and splicing distinguish lincRNAs and mRNAs. Genome Res. 27, 27–37 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liu, S. & Trapnell, C. Single-cell transcriptome sequencing: recent advances and remaining challenges. F1000Res 5, 182 (2016).

    Article  Google Scholar 

  12. Schlackow, M. et al. Distinctive patterns of transcription and RNA processing for human lincRNAs. Mol. Cell 65, 25–38 (2017). This paper applies mammalian native elongating transcript sequencing (mNET-seq), and reveals the distinct transcription patterns, chromatin tethering and degradation between mRNA and lncRNA genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yin, Y. et al. U1 snRNP regulates chromatin retention of noncoding RNAs. Nature 580, 147–150 (2020).

    Article  CAS  PubMed  Google Scholar 

  14. Vos, S. M. et al. Structure of activated transcription complex Pol II–DSIF–PAF–SPT6. Nature 560, 607–612 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Nojima, T. et al. Deregulated expression of mammalian lncRNA through loss of SPT6 induces R-loop formation, replication stress, and cellular senescence. Mol. Cell 72, 970–984.e7 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zuckerman, B. & Ulitsky, I. Predictive models of subcellular localization of long RNAs. RNA 25, 557–572 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rosenberg, A. B., Patwardhan, R. P., Shendure, J. & Seelig, G. Learning the sequence determinants of alternative splicing from millions of random sequences. Cell 163, 698–711 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Xiang, J. F. et al. Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res. 24, 513–531 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Azam, S. et al. Nuclear retention element recruits U1 snRNP components to restrain spliced lncRNAs in the nucleus. RNA Biol. 16, 1001–1009 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Shukla, C. J. et al. High-throughput identification of RNA nuclear enrichment sequences. EMBO J. 37, e98452 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lubelsky, Y. & Ulitsky, I. Sequences enriched in Alu repeats drive nuclear localization of long RNAs in human cells. Nature 555, 107–111 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hacisuleyman, E., Shukla, C. J., Weiner, C. L. & Rinn, J. L. Function and evolution of local repeats in the Firre locus. Nat. Commun. 7, 11021 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zuckerman, B., Ron, M., Mikl, M., Segal, E. & Ulitsky, I. Gene architecture and sequence composition underpin selective dependency of nuclear export of long RNAs on NXF1 and the TREX complex. Mol. Cell 79, 251–267 (2020). By systematically depleting RNA export factors, this study reveals that export of long RNAs is modulated by gene architecture, sequence composition, RNA secondary structure, sequence motifs and post-transcriptional modifications.

    Article  CAS  PubMed  Google Scholar 

  24. Carlevaro-Fita, J., Rahim, A., Guigo, R., Vardy, L. A. & Johnson, R. Cytoplasmic long noncoding RNAs are frequently bound to and degraded at ribosomes in human cells. RNA 22, 867–882 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zeng, C. & Hamada, M. Identifying sequence features that drive ribosomal association for lncRNA. BMC Genomics 19, 906 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mercer, T. R. et al. The human mitochondrial transcriptome. Cell 146, 645–658 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rackham, O. et al. Long noncoding RNAs are generated from the mitochondrial genome and regulated by nuclear-encoded proteins. RNA 17, 2085–2093 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Noh, J. H. et al. HuR and GRSF1 modulate the nuclear export and mitochondrial localization of the lncRNA RMRP. Genes Dev. 30, 1224–1239 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li, S. et al. exoRBase: a database of circRNA, lncRNA and mRNA in human blood exosomes. Nucleic Acids Res. 46, D106–D112 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Gudenas, B. L. & Wang, L. Prediction of lncRNA subcellular localization with deep learning from sequence features. Sci. Rep. 8, 16385 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Statello, L. et al. Identification of RNA-binding proteins in exosomes capable of interacting with different types of RNA: RBP-facilitated transport of RNAs into exosomes. PLoS ONE 13, e0195969 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  32. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bonetti, A. et al. RADICL-seq identifies general and cell type-specific principles of genome-wide RNA–chromatin interactions. Nat. Commun. 11, 1018 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li, X. et al. GRID-seq reveals the global RNA–chromatin interactome. Nat. Biotechnol. 35, 940–950 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Bell, J. C. et al. Chromatin-associated RNA sequencing (ChAR-seq) maps genome-wide RNA-to-DNA contacts. eLife 7, e27024 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Isoda, T. et al. Non-coding transcription instructs chromatin folding and compartmentalization to dictate enhancer–promoter communication and T cell fate. Cell 171, 103–119.e18 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mumbach, M. R. et al. HiChIRP reveals RNA-associated chromosome conformation. Nat. Methods 16, 489–492 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dueva, R. et al. Neutralization of the positive charges on histone tails by RNA promotes an open chromatin structure. Cell Chem. Biol. 26, 1436–1449.e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  39. Yang, F. et al. The lncRNA Firre anchors the inactive X chromosome to the nucleolus by binding CTCF and maintains H3K27me3 methylation. Genome Biol. 16, 52 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Saldana-Meyer, R. et al. RNA interactions are essential for CTCF-mediated genome organization. Mol. Cell 76, 412–422.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schertzer, M. D. et al. lncRNA-induced spread of polycomb controlled by genome architecture, RNA abundance, and CpG island DNA. Mol. Cell 75, 523–537.e10 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kotzin, J. J. et al. The long non-coding RNA morrbid regulates Bim and short-lived myeloid cell lifespan. Nature 537, 239–243 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Beckedorff, F. C. et al. The intronic long noncoding RNA ANRASSF1 recruits PRC2 to the RASSF1A promoter, reducing the expression of RASSF1A and increasing cell proliferation. PLoS Genet. 9, e1003705 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Marin-Bejar, O. et al. The human lncRNA LINC-PINT inhibits tumor cell invasion through a highly conserved sequence element. Genome Biol. 18, 202 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Yap, K. L. et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol. Cell 38, 662–674 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Holdt, L. M. et al. Alu elements in ANRIL non-coding RNA at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks. PLoS Genet. 9, e1003588 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Long, Y. et al. RNA is essential for PRC2 chromatin occupancy and function in human pluripotent stem cells. Nat. Genet. 52, 931–938 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Blanco, M. R. & Guttman, M. Re-evaluating the foundations of lncRNA–Polycomb function. EMBO J. 36, 964–966 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kopp, F. & Mendell, J. T. Functional classification and experimental dissection of long noncoding RNAs. Cell 172, 393–407 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Portoso, M. et al. PRC2 is dispensable for HOTAIR-mediated transcriptional repression. EMBO J. 36, 981–994 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lee, J. T. & Bartolomei, M. S. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell 152, 1308–1323 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Latos, P. A. et al. Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science 338, 1469–1472 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Pandey, R. R. et al. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol. Cell 32, 232–246 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Pintacuda, G. et al. hnRNPK recruits PCGF3/5-PRC1 to the Xist RNA B-repeat to establish Polycomb-mediated chromosomal silencing. Mol. Cell 68, 955–969.e10 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Colognori, D., Sunwoo, H., Kriz, A. J., Wang, C. Y. & Lee, J. T. Xist deletional analysis reveals an interdependency between Xist RNA and Polycomb complexes for spreading along the inactive X. Mol. Cell 74, 101–117.e10 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. McHugh, C. A. et al. The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3. Nature 521, 232–236 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jeon, Y. & Lee, J. T. YY1 tethers Xist RNA to the inactive X nucleation center. Cell 146, 119–133 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sigova, A. A. et al. Transcription factor trapping by RNA in gene regulatory elements. Science 350, 978–981 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Fanucchi, S. et al. Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nat. Genet. 51, 138–150 (2019).

    Article  CAS  PubMed  Google Scholar 

  61. Wang, K. C. et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472, 120–124 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Luo, H. et al. HOTTIP lncRNA promotes hematopoietic stem cell self-renewal leading to AML-like disease in mice. Cancer Cell 36, 645–659.e8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Jain, A. K. et al. lncPRESS1 is a p53-regulated lncRNA that safeguards pluripotency by disrupting SIRT6-mediated de-acetylation of histone H3K56. Mol. Cell 64, 967–981 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    Article  CAS  PubMed  Google Scholar 

  66. O’Leary, V. B. et al. PARTICLE, a triplex-forming long ncRNA, regulates locus-specific methylation in response to low-dose irradiation. Cell Rep. 11, 474–485 (2015).

    Article  PubMed  Google Scholar 

  67. Mondal, T. et al. MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA–DNA triplex structures. Nat. Commun. 6, 7743 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Grote, P. et al. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev. Cell 24, 206–214 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kuo, C. C. et al. Detection of RNA–DNA binding sites in long noncoding RNAs. Nucleic Acids Res. 47, e32 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Li, Y., Syed, J. & Sugiyama, H. RNA–DNA triplex formation by long noncoding RNAs. Cell Chem. Biol. 23, 1325–1333 (2016).

    Article  CAS  PubMed  Google Scholar 

  71. Blank-Giwojna, A., Postepska-Igielska, A. & Grummt, I. lncRNA KHPS1 activates a poised enhancer by triplex-dependent recruitment of epigenomic regulators. Cell Rep. 26, 2904–2915.e4 (2019).

    Article  CAS  PubMed  Google Scholar 

  72. Maldonado, R., Schwartz, U., Silberhorn, E. & Langst, G. Nucleosomes stabilize ssRNA–dsDNA triple helices in human cells. Mol. Cell 73, 1243–1254.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  73. Postepska-Igielska, A. et al. lncRNA Khps1 regulates expression of the proto-oncogene SPHK1 via triplex-mediated changes in chromatin structure. Mol. Cell 60, 626–636 (2015).

    Article  CAS  PubMed  Google Scholar 

  74. Niehrs, C. & Luke, B. Regulatory R-loops as facilitators of gene expression and genome stability. Nat. Rev. Mol. Cell Biol. 21, 167–178 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tan-Wong, S. M., Dhir, S. & Proudfoot, N. J. R-loops promote antisense transcription across the mammalian genome. Mol. Cell 76, 600–616.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Sun, Q., Csorba, T., Skourti-Stathaki, K., Proudfoot, N. J. & Dean, C. R-loop stabilization represses antisense transcription at the Arabidopsis FLC locus. Science 340, 619–621 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gibbons, H. R. et al. Divergent lncRNA GATA3-AS1 regulates GATA3 transcription in T-helper 2 cells. Front. Immunol. 9, 2512 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Boque-Sastre, R. et al. Head-to-head antisense transcription and R-loop formation promotes transcriptional activation. Proc. Natl Acad. Sci. USA 112, 5785–5790 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Arab, K. et al. GADD45A binds R-loops and recruits TET1 to CpG island promoters. Nat. Genet. 51, 217–223 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ariel, F. et al. R-loop mediated trans action of the APOLO long noncoding RNA. Mol. Cell 77, 1055–1065.e4 (2020).

    Article  CAS  PubMed  Google Scholar 

  81. Seila, A. C. et al. Divergent transcription from active promoters. Science 322, 1849–1851 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Luo, S. et al. Divergent lncRNAs regulate gene expression and lineage differentiation in pluripotent cells. Cell Stem Cell 18, 637–652 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. Gil, N. & Ulitsky, I. Regulation of gene expression by cis-acting long non-coding RNAs. Nat. Rev. Genet. 21, 102–117 (2019).

    Article  PubMed  Google Scholar 

  84. Wutz, A. Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation. Nat. Rev. Genet. 12, 542–553 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Jiang, J. et al. Translating dosage compensation to trisomy 21. Nature 500, 296–300 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Engreitz, J. M. et al. The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science 341, 1237973 (2013). This study shows that at the onset of X-chromosome inactivation, Xist binds in a sequence-independent manner to distinct regions of the X chromosome, which are brought into 3D proximity, subsequently spreading to more distal regions that reposition in the 3D space.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Giorgetti, L. et al. Structural organization of the inactive X chromosome in the mouse. Nature 535, 575–579 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Pandya-Jones, A. et al. A protein assembly mediates Xist localization and gene silencing. Nature 587, 1–7 (2020).

    Article  Google Scholar 

  89. Herzog, V. A. et al. A strand-specific switch in noncoding transcription switches the function of a Polycomb/Trithorax response element. Nat. Genet. 46, 973–981 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Alecki, C. et al. RNA–DNA strand exchange by the Drosophila Polycomb complex PRC2. Nat. Commun. 11, 1781 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rosa, S., Duncan, S. & Dean, C. Mutually exclusive sense-antisense transcription at FLC facilitates environmentally induced gene repression. Nat. Commun. 7, 13031 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Csorba, T., Questa, J. I., Sun, Q. & Dean, C. Antisense COOLAIR mediates the coordinated switching of chromatin states at FLC during vernalization. Proc. Natl Acad. Sci. USA 111, 16160–16165 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Stojic, L. et al. Transcriptional silencing of long noncoding RNA GNG12-AS1 uncouples its transcriptional and product-related functions. Nat. Commun. 7, 10406 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Thebault, P. et al. Transcription regulation by the noncoding RNA SRG1 requires Spt2-dependent chromatin deposition in the wake of RNA polymerase II. Mol. Cell. Biol. 31, 1288–1300 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Rom, A. et al. Regulation of CHD2 expression by the Chaserr long noncoding RNA gene is essential for viability. Nat. Commun. 10, 5092 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Sleutels, F., Zwart, R. & Barlow, D. P. The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature 415, 810–813 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Santoro, F. & Pauler, F. M. Silencing by the imprinted Airn macro lncRNA: transcription is the answer. Cell Cycle 12, 711–712 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Andersson, R. et al. An atlas of active enhancers across human cell types and tissues. Nature 507, 455–461 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hon, C. C. et al. An atlas of human long non-coding RNAs with accurate 5′ ends. Nature 543, 199–204 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kim, Y. J., Xie, P., Cao, L., Zhang, M. Q. & Kim, T. H. Global transcriptional activity dynamics reveal functional enhancer RNAs. Genome Res. 28, 1799–1811 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Jiao, W. et al. HPSE enhancer RNA promotes cancer progression through driving chromatin looping and regulating hnRNPU/p300/EGR1/HPSE axis. Oncogene 37, 2728–2745 (2018).

    Article  CAS  PubMed  Google Scholar 

  102. Li, W. et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498, 516–520 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kim, T. K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Marques, A. C. et al. Chromatin signatures at transcriptional start sites separate two equally populated yet distinct classes of intergenic long noncoding RNAs. Genome Biol. 14, R131 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Orom, U. A. et al. Long noncoding RNAs with enhancer-like function in human cells. Cell 143, 46–58 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. De Santa, F. et al. A large fraction of extragenic RNA Pol II transcription sites overlap enhancers. PLoS Biol. 8, e1000384 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Gil, N. & Ulitsky, I. Production of spliced long noncoding RNAs specifies regions with increased enhancer activity. Cell Syst. 7, 537–547.e3 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Tan, J. Y., Biasini, A., Young, R. S. & Marques, A. C. Splicing of enhancer-associated lincRNAs contributes to enhancer activity. Life Sci. Alliance 3, e202000663 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Amaral, P. P. et al. Genomic positional conservation identifies topological anchor point RNAs linked to developmental loci. Genome Biol. 19, 32 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Tan, J. Y. et al. cis-Acting complex-trait-associated lincRNA expression correlates with modulation of chromosomal architecture. Cell Rep. 18, 2280–2288 (2017).

    Article  CAS  PubMed  Google Scholar 

  111. Fanucchi, S. & Mhlanga, M. M. Enhancer-derived lncRNAs regulate genome architecture: fact or fiction? Trends Genet. 33, 375–377 (2017).

    Article  CAS  PubMed  Google Scholar 

  112. van Steensel, B. & Furlong, E. E. M. The role of transcription in shaping the spatial organization of the genome. Nat. Rev. Mol. Cell Biol. 20, 327–337 (2019).

    PubMed  PubMed Central  Google Scholar 

  113. Grossi, E. et al. A lncRNA–SWI/SNF complex crosstalk controls transcriptional activation at specific promoter regions. Nat. Commun. 11, 936 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tomita, S. et al. A cluster of noncoding RNAs activates the ESR1 locus during breast cancer adaptation. Nat. Commun. 6, 6966 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Dao, L. T. M. et al. Genome-wide characterization of mammalian promoters with distal enhancer functions. Nat. Genet. 49, 1073–1081 (2017).

    Article  CAS  PubMed  Google Scholar 

  116. Engreitz, J. M. et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature 539, 452–455 (2016). This paper dissects the effects in cis of 12 lncRNAs, concluding that only 5 of the lncRNAs affected the expression of the neighbouring gene, in a transcript-independent manner.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Paralkar, V. R. et al. Unlinking an lncRNA from its associated cis element. Mol. Cell 62, 104–110 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Anderson, K. M. et al. Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development. Nature 539, 433–436 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Laurent, F. et al. HAND2 target gene regulatory networks control atrioventricular canal and cardiac valve development. Cell Rep. 19, 1602–1613 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Han, X. et al. The lncRNA Hand2os1/Uph locus orchestrates heart development through regulation of precise expression of Hand2. Development 146, dev176198 (2019).

    Article  CAS  PubMed  Google Scholar 

  121. Ritter, N. et al. The lncRNA locus Handsdown regulates cardiac gene programs and is essential for early mouse development. Dev. Cell 50, 644–657.e8 (2019).

    Article  CAS  PubMed  Google Scholar 

  122. Yin, Y. et al. Opposing roles for the lncRNA Haunt and its genomic locus in regulating HOXA gene activation during embryonic stem cell differentiation. Cell Stem Cell 16, 504–516 (2015).

    Article  CAS  PubMed  Google Scholar 

  123. Banani, S. F., Lee, H. O., Hyman, A. A. & Rosen, M. K. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18, 285–298 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. West, J. A. et al. Structural, super-resolution microscopy analysis of paraspeckle nuclear body organization. J. Cell Biol. 214, 817–830 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Clemson, C. M. et al. An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. Mol. Cell 33, 717–726 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hutchinson, J. N. et al. A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains. BMC Genomics 8, 39 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Sasaki, Y. T., Ideue, T., Sano, M., Mituyama, T. & Hirose, T. MENε/β noncoding RNAs are essential for structural integrity of nuclear paraspeckles. Proc. Natl Acad. Sci. USA 106, 2525–2530 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sunwoo, H. et al. MEN ε/β nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. Genome Res. 19, 347–359 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Yamazaki, T. et al. Functional domains of NEAT1 architectural lncRNA induce paraspeckle assembly through phase separation. Mol. Cell 70, 1038–1053 e1037 (2018). This paper shows that the middle domain of NEAT1 is key for de novo assembly of the phase-separated paraspeckles.

    Article  CAS  PubMed  Google Scholar 

  130. Lin, Y., Schmidt, B. F., Bruchez, M. P. & McManus, C. J. Structural analyses of NEAT1 lncRNAs suggest long-range RNA interactions that may contribute to paraspeckle architecture. Nucleic Acids Res. 46, 3742–3752 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lu, Z. et al. RNA duplex map in living cells reveals higher-order transcriptome structure. Cell 165, 1267–1279 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wilusz, J. E. et al. A triple helix stabilizes the 3′ ends of long noncoding RNAs that lack poly(A) tails. Genes Dev. 26, 2392–2407 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Engreitz, J. M. et al. RNA–RNA interactions enable specific targeting of noncoding RNAs to nascent pre-mRNAs and chromatin sites. Cell 159, 188–199 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Tripathi, V. et al. SRSF1 regulates the assembly of pre-mRNA processing factors in nuclear speckles. Mol. Biol. Cell 23, 3694–3706 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Yang, L. et al. ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell 147, 773–788 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Arun, G. et al. Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes Dev. 30, 34–51 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Malakar, P. et al. Long noncoding RNA MALAT1 promotes hepatocellular carcinoma development by SRSF1 upregulation and mTOR activation. Cancer Res. 77, 1155–1167 (2017).

    Article  CAS  PubMed  Google Scholar 

  138. Fei, J. et al. Quantitative analysis of multilayer organization of proteins and RNA in nuclear speckles at super resolution. J. Cell Sci. 130, 4180–4192 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Cai, Z. et al. RIC-seq for global in situ profiling of RNA–RNA spatial interactions. Nature 582, 432–437 (2020).

    Article  CAS  PubMed  Google Scholar 

  140. Yin, Q. F. et al. Long noncoding RNAs with snoRNA ends. Mol. Cell 48, 219–230 (2012).

    Article  CAS  PubMed  Google Scholar 

  141. Wu, H. et al. Unusual processing generates SPA lncRNAs that sequester multiple RNA binding proteins. Mol. Cell 64, 534–548 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Yap, K. et al. A short tandem repeat-enriched RNA assembles a nuclear compartment to control alternative splicing and promote cell survival. Mol. Cell 72, 525–540.e13 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Jolly, C., Usson, Y. & Morimoto, R. I. Rapid and reversible relocalization of heat shock factor 1 within seconds to nuclear stress granules. Proc. Natl Acad. Sci. USA 96, 6769–6774 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Weighardt, F. et al. A novel hnRNP protein (HAP/SAF-B) enters a subset of hnRNP complexes and relocates in nuclear granules in response to heat shock. J. Cell Sci. 112, 1465–1476 (1999).

    Article  CAS  PubMed  Google Scholar 

  145. Denegri, M. et al. Stress-induced nuclear bodies are sites of accumulation of pre-mRNA processing factors. Mol. Biol. Cell 12, 3502–3514 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Metz, A., Soret, J., Vourc’h, C., Tazi, J. & Jolly, C. A key role for stress-induced satellite III transcripts in the relocalization of splicing factors into nuclear stress granules. J. Cell Sci. 117, 4551–4558 (2004).

    Article  CAS  PubMed  Google Scholar 

  147. Jolly, C. et al. Stress-induced transcription of satellite III repeats. J. Cell Biol. 164, 25–33 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Ninomiya, K. et al. lncRNA-dependent nuclear stress bodies promote intron retention through SR protein phosphorylation. EMBO J. 39, e102729 (2020).

    Article  CAS  PubMed  Google Scholar 

  149. Audas, T. E., Jacob, M. D. & Lee, S. Immobilization of proteins in the nucleolus by ribosomal intergenic spacer noncoding RNA. Mol. Cell 45, 147–157 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. Wang, M. et al. Stress-induced low complexity RNA activates physiological amyloidogenesis. Cell Rep. 24, 1713–1721.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Hacisuleyman, E. et al. Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre. Nat. Struct. Mol. Biol. 21, 198–206 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Lewandowski, J. P. et al. The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis. Nat. Commun. 10, 5137 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Maass, P. G., Barutcu, A. R., Weiner, C. L. & Rinn, J. L. Inter-chromosomal contact properties in live-cell imaging and in Hi-C. Mol. Cell 69, 1039–1045.e3 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Hartford, C. C. R. & Lal, A. When long noncoding becomes protein coding. Mol. Cell. Biol. 40, e00528-19 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Romero-Barrios, N., Legascue, M. F., Benhamed, M., Ariel, F. & Crespi, M. Splicing regulation by long noncoding RNAs. Nucleic Acids Res. 46, 2169–2184 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Lee, S. et al. Noncoding RNA NORAD regulates genomic stability by sequestering PUMILIO proteins. Cell 164, 69–80 (2016).

    Article  CAS  PubMed  Google Scholar 

  157. Tichon, A., Perry, R. B., Stojic, L. & Ulitsky, I. SAM68 is required for regulation of Pumilio by the NORAD long noncoding RNA. Genes Dev. 32, 70–78 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Miller, M. A. & Olivas, W. M. Roles of Puf proteins in mRNA degradation and translation. Wiley Interdiscip. Rev. RNA 2, 471–492 (2011).

    Article  CAS  PubMed  Google Scholar 

  159. Liu, B. et al. A cytoplasmic NF-κB interacting long noncoding RNA blocks IκB phosphorylation and suppresses breast cancer metastasis. Cancer Cell 27, 370–381 (2015).

    Article  CAS  PubMed  Google Scholar 

  160. Kretz, M. et al. Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature 493, 231–235 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. Gong, C. & Maquat, L. E. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature 470, 284–288 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Wang, J., Gong, C. & Maquat, L. E. Control of myogenesis by rodent SINE-containing lncRNAs. Genes Dev. 27, 793–804 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Eckhart, L., Lachner, J., Tschachler, E. & Rice, R. H. TINCR is not a non-coding RNA but encodes a protein component of cornified epidermal keratinocytes. Exp. Dermatol. 29, 376–379 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Carrieri, C. et al. Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature 491, 454–457 (2012).

    Article  CAS  PubMed  Google Scholar 

  165. Cesana, M. et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147, 358–369 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Bosson, A. D., Zamudio, J. R. & Sharp, P. A. Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition. Mol. Cell 56, 347–359 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Denzler, R., Agarwal, V., Stefano, J., Bartel, D. P. & Stoffel, M. Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. Mol. Cell 54, 766–776 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Grelet, S. et al. A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression. Nat. Cell Biol. 19, 1105–1115 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Fatima, F. & Nawaz, M. Vesiculated long non-coding RNAs: offshore packages deciphering trans-regulation between cells, cancer progression and resistance to therapies. Noncoding RNA 3, 10 (2017).

    PubMed  PubMed Central  Google Scholar 

  171. Zhao, Y., Sun, L., Wang, R. R., Hu, J. F. & Cui, J. The effects of mitochondria-associated long noncoding RNAs in cancer mitochondria: new players in an old arena. Crit. Rev. Oncol. Hematol. 131, 76–82 (2018).

    Article  PubMed  Google Scholar 

  172. Leucci, E. et al. Melanoma addiction to the long non-coding RNA SAMMSON. Nature 531, 518–522 (2016).

    Article  CAS  PubMed  Google Scholar 

  173. Vendramin, R. et al. SAMMSON fosters cancer cell fitness by concertedly enhancing mitochondrial and cytosolic translation. Nat. Struct. Mol. Biol. 25, 1035–1046 (2018). This study discovers that the mitochondrially localized oncogenic lncRNA SAMMSON modulates RNA–protein complex formation in distinct cellular compartments, including in mitochondria, the cytosol and the nucleus to promote cell growth.

    Article  CAS  PubMed  Google Scholar 

  174. Fatica, A. & Bozzoni, I. Long non-coding RNAs: new players in cell differentiation and development. Nat. Rev.Genet. 15, 7–21 (2014).

    Article  CAS  PubMed  Google Scholar 

  175. Sweta, S., Dudnakova, T., Sudheer, S., Baker, A. H. & Bhushan, R. Importance of long non-coding RNAs in the development and disease of skeletal muscle and cardiovascular lineages. Front. Cell Dev. Biol. 7, 228 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Hobuss, L., Bar, C. & Thum, T. Long non-coding RNAs: at the heart of cardiac dysfunction? Front. Physiol. 10, 30 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Sun, L. & Lin, J. D. Function and mechanism of long noncoding RNAs in adipocyte biology. Diabetes 68, 887–896 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Chen, Y. G., Satpathy, A. T. & Chang, H. Y. Gene regulation in the immune system by long noncoding RNAs. Nat. Immunol. 18, 962–972 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Hezroni, H., Perry, R. B. T. & Ulitsky, I. Long noncoding RNAs in development and regeneration of the neural lineage. Cold Spring Harb. Symp. Quant. Biol. 84, 165–177 (2019).

    Article  PubMed  Google Scholar 

  180. Briggs, J. A., Wolvetang, E. J., Mattick, J. S., Rinn, J. L. & Barry, G. Mechanisms of long non-coding RNAs in mammalian nervous system development, plasticity, disease, and evolution. Neuron 88, 861–877 (2015).

    Article  CAS  PubMed  Google Scholar 

  181. Sauvageau, M. et al. Multiple knockout mouse models reveal lincRNAs are required for life and brain development. eLife 2, e01749 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  182. He, D. et al. lncRNA functional networks in oligodendrocytes reveal stage-specific myelination control by an lncOL1/Suz12 complex in the CNS. Neuron 93, 362–378 (2017).

    Article  CAS  PubMed  Google Scholar 

  183. Perry, R. B., Hezroni, H., Goldrich, M. J. & Ulitsky, I. Regulation of neuroregeneration by long noncoding RNAs. Mol. Cell 72, 553–567.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Wei, C. W., Luo, T., Zou, S. S. & Wu, A. S. The role of long noncoding RNAs in central nervous system and neurodegenerative diseases. Front. Behav. Neurosci. 12, 175 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Faghihi, M. A. et al. Evidence for natural antisense transcript-mediated inhibition of microRNA function. Genome Biol. 11, R56 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Feng, L. et al. Plasma long non-coding RNA BACE1 as a novel biomarker for diagnosis of Alzheimer disease. BMC Neurol. 18, 4 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Luo, M. et al. Long non-coding RNAs control hematopoietic stem cell function. Cell Stem Cell 16, 426–438 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Atianand, M. K. et al. A long noncoding RNA lincRNA-EPS acts as a transcriptional brake to restrain inflammation. Cell 165, 1672–1685 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Castellanos-Rubio, A. et al. A long noncoding RNA associated with susceptibility to celiac disease. Science 352, 91–95 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Peng, X. et al. Unique signatures of long noncoding RNA expression in response to virus infection and altered innate immune signaling. mBio 1, e00206–e00210 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Hadjicharalambous, M. R. & Lindsay, M. A. Long non-coding RNAs and the innate immune response. Noncoding RNA 5, 34 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Kambara, H. et al. Negative regulation of the interferon response by an interferon-induced long non-coding RNA. Nucleic Acids Res. 42, 10668–10680 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Carnero, E. et al. Long noncoding RNA EGOT negatively affects the antiviral response and favors HCV replication. EMBO Rep. 17, 1013–1028 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Gao, Y. et al. Lnc2Cancer v2.0: updated database of experimentally supported long non-coding RNAs in human cancers. Nucleic Acids Res. 47, D1028–D1033 (2019).

    Article  CAS  PubMed  Google Scholar 

  195. Carlevaro-Fita, J. et al. Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis. Commun. Biol. 3, 56 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Sanchez, Y. et al. Genome-wide analysis of the human p53 transcriptional network unveils a lncRNA tumour suppressor signature. Nat. Commun. 5, 5812 (2014). This study shows that following DNA damage, p53 directly activates the expression of dozens of lncRNAs in human cells, which is required for the complete tumour suppressor response of p53.

    Article  CAS  PubMed  Google Scholar 

  197. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Hart, J. R., Roberts, T. C., Weinberg, M. S., Morris, K. V. & Vogt, P. K. MYC regulates the non-coding transcriptome. Oncotarget 5, 12543–12554 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Kim, T. et al. Role of MYC-regulated long noncoding RNAs in cell cycle regulation and tumorigenesis. J. Natl Cancer Inst. 107, https://doi.org/10.1093/jnci/dju505 (2015).

  200. Chakravarty, D. et al. The oestrogen receptor α-regulated lncRNA NEAT1 is a critical modulator of prostate cancer. Nat. Commun. 5, 5383 (2014).

    Article  CAS  PubMed  Google Scholar 

  201. Trimarchi, T. et al. Genome-wide mapping and characterization of notch-regulated long noncoding RNAs in acute leukemia. Cell 158, 593–606 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Groff, A. F. et al. In vivo characterization of Linc-p21 reveals functional cis-regulatory DNA elements. Cell Rep. 16, 2178–2186 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Dimitrova, N. et al. lincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint. Mol. Cell 54, 777–790 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Hung, T. et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat. Genet. 43, 621–629 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Schmitt, A. M. et al. An inducible long noncoding RNA amplifies DNA damage signaling. Nat. Genet. 48, 1370–1376 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Hu, W. L. et al. GUARDIN is a p53-responsive long non-coding RNA that is essential for genomic stability. Nat. Cell Biol. 20, 492–502 (2018).

    Article  PubMed  Google Scholar 

  207. Zhou, Y., Zhang, X. & Klibanski, A. MEG3 noncoding RNA: a tumor suppressor. J. Mol. Endocrinol. 48, R45–R53 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Uroda, T. et al. Conserved pseudoknots in lncRNA MEG3 are essential for stimulation of the p53 pathway. Mol. Cell 75, 982–995.e9 (2019). This study identifies conserved structural elements in the lncRNA MEG3 that are required for the activation of the p53 response by the lncRNA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Winkle, M. et al. Long noncoding RNAs as a novel component of the Myc transcriptional network. FASEB J. 29, 2338–2346 (2015).

    Article  CAS  PubMed  Google Scholar 

  210. Tseng, Y. Y. et al. PVT1 dependence in cancer with MYC copy-number increase. Nature 512, 82–86 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Wang, Z. et al. lncRNA epigenetic landscape analysis identifies EPIC1 as an oncogenic lncRNA that interacts with MYC and promotes cell-cycle progression in cancer. Cancer Cell 33, 706–720.e9 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Jia, L. et al. Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet. 5, e1000597 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Sur, I., Tuupanen, S., Whitington, T., Aaltonen, L. A. & Taipale, J. Lessons from functional analysis of genome-wide association studies. Cancer Res. 73, 4180–4184 (2013).

    Article  CAS  PubMed  Google Scholar 

  214. Ling, H. et al. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res. 23, 1446–1461 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Kim, T. et al. Long-range interaction and correlation between MYC enhancer and oncogenic long noncoding RNA CARLo-5. Proc. Natl Acad. Sci. USA 111, 4173–4178 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Prensner, J. R. et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat. Biotechnol. 29, 742–749 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Yang, L. et al. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 500, 598–602 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Cui, M. et al. Long non-coding RNA PVT1 and cancer. Biochem. Biophys. Res. Commun. 471, 10–14 (2016).

    Article  CAS  PubMed  Google Scholar 

  219. Cho, S. W. et al. Promoter of lncRNA gene PVT1 is a tumor-suppressor DNA boundary element. Cell 173, 1398–1412.e22 (2018). This study shows that a DNA element within the promoter of the lncRNA PVT1 regulates the expression of MYC in a lncRNA-independent manner.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Lee, J. S. & Mendell, J. T. Antisense-mediated transcript knockdown triggers premature transcription termination. Mol. Cell 77, 1044–1054.e3 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Lai, F., Damle, S. S., Ling, K. K. & Rigo, F. Directed RNase H cleavage of nascent transcripts causes transcription termination. Mol. Cell 77, 1032–1043.e4 (2020). Together with Lee and Mendell (2020), this paper shows that the RNase H-mediated cleavage of transcripts guided by ASOs leads to transcriptional termination, which should be considered when interpreting the transcription phenotypes.

    Article  CAS  PubMed  Google Scholar 

  222. Monia, B. P. et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as antisense inhibitors of gene expression. J. Biol. Chem. 268, 14514–14522 (1993).

    Article  CAS  PubMed  Google Scholar 

  223. Seth, P. P. et al. Design, synthesis and evaluation of constrained methoxyethyl (cMOE) and constrained ethyl (cEt) nucleoside analogs. Nucleic Acids Symp. Ser. 52, 553–554 (2008).

    Article  CAS  Google Scholar 

  224. Dassie, J. P. & Giangrande, P. H. Current progress on aptamer-targeted oligonucleotide therapeutics. Ther. Deliv. 4, 1527–1546 (2013).

    Article  CAS  PubMed  Google Scholar 

  225. Dhuri, K. et al. Antisense oligonucleotides: an emerging area in drug discovery and development. J. Clin. Med. 9, 2004 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Warner, K. D., Hajdin, C. E. & Weeks, K. M. Principles for targeting RNA with drug-like small molecules. Nat. Rev. Drug Discov. 17, 547–558 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Hawkes, E. J. et al. COOLAIR antisense RNAs form evolutionarily conserved elaborate secondary structures. Cell Rep. 16, 3087–3096 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Novikova, I. V., Hennelly, S. P. & Sanbonmatsu, K. Y. Structural architecture of the human long non-coding RNA, steroid receptor RNA activator. Nucleic Acids Res. 40, 5034–5051 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Somarowthu, S. et al. HOTAIR forms an intricate and modular secondary structure. Mol. Cell 58, 353–361 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Perez-Pinera, P. et al. Synergistic and tunable human gene activation by combinations of synthetic transcription factors. Nat. Methods 10, 239–242 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Kim, D. N. et al. Zinc-finger protein CNBP alters the 3-D structure of lncRNA Braveheart in solution. Nat. Commun. 11, 148 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Ran, F. A. et al. Genome engineering using the CRISPR–Cas9 system. Nat. Protoc. 8, 2281–2308 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Qi, L. S. et al. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152, 1173–1183 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Perez-Pinera, P. et al. RNA-guided gene activation by CRISPR–Cas9-based transcription factors. Nat. Methods 10, 973–976 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Abudayyeh, O. O. et al. RNA targeting with CRISPR–Cas13. Nature 550, 280–284 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  236. Esposito, R. et al. Hacking the cancer genome: profiling therapeutically actionable long non-coding RNAs using CRISPR–Cas9 screening. Cancer Cell 35, 545–557 (2019).

    Article  CAS  PubMed  Google Scholar 

  237. Kirk, J. M. et al. Functional classification of long non-coding RNAs by k-mer content. Nat. Genet. 50, 1474–1482 (2018). This study shows that lncRNAs can be classified into functional groups based on their content of 6-nucleotide k-mers, and demonstrates experimentally the k-mer dependence of gene repression by lncRNAs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Arab, K. et al. Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A. Mol. Cell 55, 604–614 (2014).

    Article  CAS  PubMed  Google Scholar 

  239. Kong, Y., Hsieh, C. H. & Alonso, L. C. ANRIL: a lncRNA at the CDKN2A/B locus with roles in cancer and metabolic disease. Front. Endocrinol. 9, 405 (2018).

    Article  Google Scholar 

  240. Mira-Bontenbal, H. & Gribnau, J. New Xist-interacting proteins in X-chromosome inactivation. Curr. Biol. 26, R338–R342 (2016).

    Article  CAS  PubMed  Google Scholar 

  241. Duszczyk, M. M., Wutz, A., Rybin, V. & Sattler, M. The Xist RNA A-repeat comprises a novel AUCG tetraloop fold and a platform for multimerization. RNA 17, 1973–1982 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Lu, Z., Carter, A. C. & Chang, H. Y. Mechanistic insights in X-chromosome inactivation. Philos. Trans. R. Soc. Lond. B Biol. Sci. 372, 20160356 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  243. Chaligne, R. & Heard, E. X-chromosome inactivation in development and cancer. FEBS Lett. 588, 2514–2522 (2014).

    Article  CAS  PubMed  Google Scholar 

  244. Yildirim, E. et al. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 152, 727–742 (2013).

    Article  CAS  PubMed  Google Scholar 

  245. Chen, D. L. et al. Long noncoding RNA XIST expedites metastasis and modulates epithelial–mesenchymal transition in colorectal cancer. Cell Death Dis. 8, e3011 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Marcho, C., Bevilacqua, A., Tremblay, K. D. & Mager, J. Tissue-specific regulation of Igf2r/Airn imprinting during gastrulation. Epigenetics Chromatin 8, 10 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  247. Mohammad, F., Mondal, T., Guseva, N., Pandey, G. K. & Kanduri, C. Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt1. Development 137, 2493–2499 (2010).

    Article  CAS  PubMed  Google Scholar 

  248. Higashimoto, K., Soejima, H., Saito, T., Okumura, K. & Mukai, T. Imprinting disruption of the CDKN1C/KCNQ1OT1 domain: the molecular mechanisms causing Beckwith–Wiedemann syndrome and cancer. Cytogenet. Genome Res. 113, 306–312 (2006).

    Article  CAS  PubMed  Google Scholar 

  249. Liu, Z., Chen, Q. & Hann, S. S. The functions and oncogenic roles of CCAT1 in human cancer. Biomed. Pharmacother. 115, 108943 (2019).

    Article  CAS  PubMed  Google Scholar 

  250. Sharma, U. et al. Long non-coding RNA TINCR as potential biomarker and therapeutic target for cancer. Life Sci. 257, 118035 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Huang, D. et al. NKILA lncRNA promotes tumor immune evasion by sensitizing T cells to activation-induced cell death. Nat. Immunol. 19, 1112–1125 (2018).

    Article  CAS  PubMed  Google Scholar 

  252. Meng, Q., Ren, M., Li, Y. & Song, X. lncRNA-RMRP acts as an oncogene in lung cancer. PLoS ONE 11, e0164845 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  253. Rosenbluh, J. et al. RMRP is a non-coding RNA essential for early murine development. PLoS ONE 6, e26270 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Dong, P. et al. Long non-coding RNA NEAT1: a novel target for diagnosis and therapy in human tumors. Front. Genet. 9, 471 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Adriaens, C. et al. p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity. Nat. Med. 22, 861–868 (2016).

    Article  CAS  PubMed  Google Scholar 

  256. Nakagawa, S. et al. The lncRNA Neat1 is required for corpus luteum formation and the establishment of pregnancy in a subpopulation of mice. Development 141, 4618–4627 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Engreitz, J. M. et al. RNA–RNA interactions enable specific targeting of noncoding RNAs to nascent pre-mRNAs and chromatin sites. Cell 159, 188–199 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Michalik, K. M. et al. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ. Res. 114, 1389–1397 (2014).

    Article  CAS  PubMed  Google Scholar 

  260. Shi, X. et al. lncRNA FIRRE is activated by MYC and promotes the development of diffuse large B-cell lymphoma via Wnt/β-catenin signaling pathway. Biochem. Biophys. Res. Commun. 510, 594–600 (2019).

    Article  CAS  PubMed  Google Scholar 

  261. Hung, T. et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat. Genet. 43, 621–629 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Munschauer, M. et al. The NORAD lncRNA assembles a topoisomerase complex critical for genome stability. Nature 561, 132–136 (2018).

    Article  CAS  PubMed  Google Scholar 

  263. Yang, Z. et al. Noncoding RNA activated by DNA damage (NORAD): biologic function and mechanisms in human cancers. Clin. Chim. Acta 489, 5–9 (2019).

    Article  CAS  PubMed  Google Scholar 

  264. Kopp, F. et al. PUMILIO hyperactivity drives premature aging of Norad-deficient mice. eLife 8, e42650 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  265. Marchese, F. P. et al. A long noncoding RNA regulates sister chromatid cohesion. Mol. Cell 63, 397–407 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Melo, C. A. et al. eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol. Cell 49, 524–535 (2013).

    Article  CAS  PubMed  Google Scholar 

  267. Li, W. et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498, 516–520 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Krause, H. M. New and prospective roles for lncRNAs in organelle formation and function. Trends Genet. 34, 736–745 (2018).

    Article  CAS  PubMed  Google Scholar 

  269. Wang, X., McLachlan, J., Zamore, P. D. & Hall, T. M. Modular recognition of RNA by a human Pumilio-homology domain. Cell 110, 501–512 (2002).

    Article  CAS  PubMed  Google Scholar 

  270. Cai, Z. et al. RIC-seq for global in situ profiling of RNA–RNA spatial interactions. Nature https://doi.org/10.1038/s41586-020-2249-1 (2020). This paper presents 3D RNA interaction maps in human cells generated with RIC-seq showing lncRNA involvement in several structural interactions, including the connections between promoters and enhancers required for enhancer function.

    Article  PubMed  PubMed Central  Google Scholar 

  271. Azzalin, C. M., Reichenbach, P., Khoriauli, L., Giulotto, E. & Lingner, J. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 318, 798–801 (2007).

    Article  CAS  PubMed  Google Scholar 

  272. Flynn, R. L. et al. TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature 471, 532–536 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Montero, J. J. et al. TERRA recruitment of Polycomb to telomeres is essential for histone trymethylation marks at telomeric heterochromatin. Nat. Commun. 9, 1548 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  274. Deng, Z., Norseen, J., Wiedmer, A., Riethman, H. & Lieberman, P. M. TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres. Mol. Cell 35, 403–413 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Balk, B. et al. Telomeric RNA–DNA hybrids affect telomere-length dynamics and senescence. Nat. Struct. Mol. Biol. 20, 1199–1205 (2013).

    Article  CAS  PubMed  Google Scholar 

  276. Arora, R. et al. RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells. Nat. Commun. 5, 5220 (2014).

    Article  CAS  PubMed  Google Scholar 

  277. Porro, A. et al. Functional characterization of the TERRA transcriptome at damaged telomeres. Nat. Commun. 5, 5379 (2014).

    Article  CAS  PubMed  Google Scholar 

  278. Verdel, A. et al. RNAi-mediated targeting of heterochromatin by the RITS complex. Science 303, 672–676 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Blower, M. D. Centromeric transcription regulates Aurora-B localization and activation. Cell Rep. 15, 1624–1633 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Liu, H. et al. Mitotic transcription installs Sgo1 at centromeres to coordinate chromosome segregation. Mol. Cell 59, 426–436 (2015).

    Article  CAS  PubMed  Google Scholar 

  281. Donley, N., Smith, L. & Thayer, M. J. ASAR15, a cis-acting locus that controls chromosome-wide replication timing and stability of human chromosome 15. PLoS Genet. 11, e1004923 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  282. Donley, N., Stoffregen, E. P., Smith, L., Montagna, C. & Thayer, M. J. Asynchronous replication, mono-allelic expression, and long range cis-effects of ASAR6. PLoS Genet. 9, e1003423 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Platt, E. J., Smith, L. & Thayer, M. J. L1 retrotransposon antisense RNA within ASAR lncRNAs controls chromosome-wide replication timing. J. Cell Biol. 217, 541–553 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Heskett, M., Smith, L. G., Spellman, P. & Thayer, M. Reciprocal monoallelic expression of ASAR lncRNA genes controls replication timing of human chromosome 6. RNA 26, 724–738 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    Article  CAS  PubMed  Google Scholar 

  286. Keskin, H., Meers, C. & Storici, F. Transcript RNA supports precise repair of its own DNA gene. RNA Biol. 13, 157–165 (2016).

    Article  PubMed  Google Scholar 

  287. Keskin, H. et al. Transcript-RNA-templated DNA recombination and repair. Nature 515, 436–439 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Chakraborty, A. et al. Classical non-homologous end-joining pathway utilizes nascent RNA for error-free double-strand break repair of transcribed genes. Nat. Commun. 7, 13049 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Wei, L. et al. DNA damage during the G0/G1 phase triggers RNA-templated, Cockayne syndrome B-dependent homologous recombination. Proc. Natl Acad. Sci. USA 112, E3495–E3504 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Michelini, F. et al. Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks. Nat. Cell Biol. 19, 1400–1411 (2017). This paper describes the production of DNA damage-induced lncRNAs by Pol II at DNA breaks, which serve as precursors for small RNAs and recruiters of 53BP1 for DNA repair.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. Betts, J. A. et al. Long noncoding RNAs CUPID1 and CUPID2 mediate breast cancer risk at 11q13 by modulating the response to DNA damage. Am. J. Hum. Genet. 101, 255–266 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Sakthianandeswaren, A., Liu, S. & Sieber, O. M. Long noncoding RNA LINP1: scaffolding non-homologous end joining. Cell Death Discov. 2, 16059 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Chaudhary, R. et al. Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in human colorectal cancer cells by binding to Matrin 3. eLife 6, e23244 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  294. Sharma, V. et al. A BRCA1-interacting lncRNA regulates homologous recombination. EMBO Rep. 16, 1520–1534 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. Bharti, S. K. et al. Molecular functions and cellular roles of the ChlR1 (DDX11) helicase defective in the rare cohesinopathy Warsaw breakage syndrome. Cell. Mol. Life Sci. 71, 2625–2639 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

M.H. is supported by Fondo Europeo de Desarrollo Regional/Ministerio de Ciencia, Innovación y Universidades — Agencia Estatal de Investigación grant BFU2017–82773-P, European Research Council Consolidator grant 771425 and Worldwide Cancer Research grant 20-0204. L.-L. C. is supported by National Natural Science Foundation of China grants 91940303, 31861143025 and 31725009 and HHMI International Research Scholar Program grant 55008728.

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Author notes

  1. These authors contributed equally: Luisa Statello, Chun-Jie Guo.

Authors and Affiliations

  1. Center for Applied Medical Research, University of Navarra, Pamplona, Spain

    Luisa Statello & Maite Huarte

  2. Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain

    Luisa Statello & Maite Huarte

  3. State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Chun-Jie Guo & Ling-Ling Chen

  4. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Ling-Ling Chen

  5. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China

    Ling-Ling Chen

Authors
  1. Luisa Statello
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  2. Chun-Jie Guo
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Related links

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Supplementary information

Glossary

Enhancer RNAs

Relatively short (≤2 kb) long non-coding RNAs that are bidirectionally transcribed from enhancer regions, are not consistently spliced or polyadenylated and are rapidly degraded.

Promoter upstream transcripts

Transcripts that are divergently transcribed upstream of active gene promoters and rapidly degraded by the RNA exosome complex.

RNA exosome

A complex of ribonucleases that regulates the degradation of multiple types of RNA in eukaryotes.

Integrator

A multi-protein complex associated with RNA polymerase II that modulates the fate of many nascent RNAs, including mRNAs, enhancer RNAs and promoter upstream transcripts.

R-loops

RNA–DNA hybrids formed by Watson–Crick interactions predominantly in cis, but also in trans through homologous recombination.

Exosomes

Small vesicles secreted from cells that contain various RNAs and proteins.

Triple helices

RNA–DNA structures forming when a polypurine motif of an RNA interacts with the major groove of a DNA double helix through Hoogsteen or reverse Hoogsteen base pairing; stabilized by nucleosomal organization.

Paraspeckles

Nuclear condensates enriched in several proteins, a subset of mRNAs and even some primary microRNAs, which are involved in various biological processes.

Nuclear speckles

Nuclear domains in mammalian cells enriched in pre-mRNA splicing factors, located in inter-chromosomal regions.

RNA in situ conformation sequencing

(RIC-seq). A method of determining intramolecular and intermolecular RNA–RNA interactions.

Small nucleolar RNA-related lncRNAs

Unusually processed long non-coding RNAs (lncRNAs) that are derived from introns and contain small nucleolar RNAs at both ends.

5′ small nucleolar RNA-capped and 3′ polyadenylated lncRNAs

(SPAs). Unusually processed long non-coding RNAs (lncRNAs) that are derived from polycistronic transcripts, capped by small nucleolar RNAs at their 5′ end and polyadenylated at their 3′ end.

Perinucleolar compartment

A nuclear body at the periphery of the nucleolus. The perinucleolar compartment is a dynamic structure and is highly enriched in RNA-binding proteins and RNA polymerase III.

Nuclear stress bodies

Nuclear condensates that are formed under different stresses, such as heat shock and DNA damage.

Serine and arginine-rich (SR) proteins

RNA binding proteins known as regulators of constitutive and alternative splicing.

Antisense oligonucleotides

(ASOs). Single-stranded deoxyribonucleotides complementary to a target RNA. Antisense oligonucleotides can affect RNA expression through various mechanisms, including modulation of splicing, steric blockade and cleavage by RNase H.

Fused aptamers

Chimeric molecules comprising at least one aptamer — a single-stranded synthetic oligonucleotide that folds into a defined architecture to specifically bind with high affinity to an RNA, a protein or another ligand — and another molecule with different biological properties.

k-mer

A short (3–8 nucleotides) sequence motif, often mediating the interaction of nucleic acids with proteins or other molecules. k specifies the length of the motif.

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Statello, L., Guo, CJ., Chen, LL. et al. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol 22, 96–118 (2021). https://doi.org/10.1038/s41580-020-00315-9

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