Diverging RNPs: Toward Understanding lncRNA-Protein Interactions and Functions

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1203)


RNA-protein interactions are essential to a variety of biological processes. The realization that mammalian genomes are pervasively transcribed brought a tidal wave of tens of thousands of newly identified long noncoding RNAs (lncRNAs) and raised questions about their purpose in cells. The vast majority of lncRNAs have yet to be studied, and it remains to be determined to how many of these transcripts a function can be ascribed. However, results gleaned from studying a handful of these macromolecules have started to reveal common themes of biological function and mechanism of action involving intricate RNA-protein interactions. Some lncRNAs were shown to regulate the chromatin and transcription of distant and neighboring genes in the nucleus, while others regulate the translation or localization of proteins in the cytoplasm. Some lncRNAs were found to be crucial during development, while mutations and aberrant expression of others have been associated with several types of cancer and a plethora of diseases. Over the last few years, the establishment of new technologies has been key in providing the tools to decode the rules governing lncRNA-protein interactions and functions. This chapter will highlight the general characteristics of lncRNAs, their function, and their mode of action, with a special focus on protein interactions. It will also describe the methods at the disposition of scientists to help them cross this next frontier in our understanding of lncRNA biology.


Long noncoding RNAs RNA-protein interactions RNA biology Ribonucleoprotein complexes Functional RNAs 



I would like to thank Drs Marlene Oeffinger and Daniel Zenklusen for insightful discussions and critically reading the manuscript as well as members of my laboratory for their input.


M.S. is a Junior Research Scholar of the Fonds de Recherche du Québéc Santé (FRQS). This work is also supported by a Canadian Institutes of Health Research (CIHR) Project Grant, a National Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, and a Canadian Foundation for Innovation (CFI) John R. Evans Leaders Fund Grant to M.S.


  1. Andersen RE, Hong S, Lim JJ, Cui M, Harpur BA, Hwang E, Delgado RN, Ramos AD, Liu S, Blencowe BJ et al (2019) The long noncoding RNA Pnky is a trans-acting regulator of cortical development In Vivo. Dev cell 49:632–642.e7PubMedCrossRefPubMedCentralGoogle Scholar
  2. Anderson DM, Anderson KM, Chang C-L, Makarewich CA, Nelson BR, McAnally JR, Kasaragod P, Shelton JM, Liou J, Bassel-Duby R et al (2015) A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell 160:595–606PubMedPubMedCentralCrossRefGoogle Scholar
  3. Arun G, Diermeier S, Akerman M, Chang K-C, Wilkinson EJ, Hearn S, Kim Y, MacLeod RA, Krainer AR, Norton L et al (2016) Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes Dev 30:34–51PubMedPubMedCentralCrossRefGoogle Scholar
  4. Atianand MK, Hu W, Satpathy AT, Shen Y, Ricci EP, Alvarez-Dominguez JR, Bhatta A, Schattgen SA, McGowan JD, Blin J et al (2016) A long noncoding RNA lincRNA-EPS acts as a transcriptional brake to restrain inflammation. Cell 165:1672–1685PubMedPubMedCentralCrossRefGoogle Scholar
  5. Avner P, Heard E (2001) X-chromosome inactivation: counting, choice and initiation. Nat Rev Genet 2:59CrossRefGoogle Scholar
  6. Balk B, Maicher A, Dees M, Klermund J, Luke-Glaser S, Bender K, Luke B (2013) Telomeric RNA-DNA hybrids affect telomere-length dynamics and senescence. Nat Struct Mol Biol 20:1199–1205PubMedCrossRefPubMedCentralGoogle Scholar
  7. Bassett AR, Akhtar A, Barlow DP, Bird AP, Brockdorff N, Duboule D, Ephrussi A, Ferguson-Smith AC, Gingeras TR, Haerty W et al (2014) Considerations when investigating lncRNA function in vivo. Elife 3:e03058PubMedPubMedCentralCrossRefGoogle Scholar
  8. Beletskii A, Hong Y-K, Pehrson J, Egholm M, Strauss WM (2001) PNA interference mapping demonstrates functional domains in the noncoding RNA Xist. Proc Natl Acad Sci U S A 98:9215–9220PubMedPubMedCentralCrossRefGoogle Scholar
  9. Blank-Giwojna A, Postepska-Igielska A, Grummt I (2019) lncRNA KHPS1 activates a poised enhancer by triplex-dependent recruitment of epigenomic regulators. Cell Rep 26:2904–2915.e4PubMedCrossRefPubMedCentralGoogle Scholar
  10. Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, Rinn JL (2011) Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev 25:1915–1927PubMedPubMedCentralCrossRefGoogle Scholar
  11. Capshew CR, Dusenbury KL, Hundley HA (2012) Inverted Alu dsRNA structures do not affect localization but can alter translation efficiency of human mRNAs independent of RNA editing. Nucleic Acids Res 40:8637–8645PubMedPubMedCentralCrossRefGoogle Scholar
  12. Carlevaro-Fita J, Polidori T, Das M, Navarro C, Zoller TI, Johnson R (2019) Ancient exapted transposable elements promote nuclear enrichment of human long noncoding RNAs. Genome Res 29:208–222PubMedPubMedCentralCrossRefGoogle Scholar
  13. Carrieri C, Cimatti L, Biagioli M, Beugnet A, Zucchelli S, Fedele S, Pesce E, Ferrer I, Collavin L, Santoro C et al (2012) Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature 491:454PubMedCrossRefPubMedCentralGoogle Scholar
  14. Chen L-L, Carmichael GG (2009) Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: functional role of a nuclear noncoding RNA. Mol Cell 35:467–478PubMedPubMedCentralCrossRefGoogle Scholar
  15. Chen L, DeCerbo JN, Carmichael GG (2008) Alu element-mediated gene silencing. EMBO J 27:1694–1705PubMedPubMedCentralCrossRefGoogle Scholar
  16. Chen C-K, Blanco M, Jackson C, Aznauryan E, Ollikainen N, Surka C, Chow A, Cerase A, McDonel P, Guttman M (2016a) Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing. Science 354:468–472PubMedCrossRefPubMedCentralGoogle Scholar
  17. Chen J, Shishkin AA, Zhu X, Kadri S, Maza I, Guttman M, Hanna JH, Regev A, Garber M (2016b) Evolutionary analysis across mammals reveals distinct classes of long non-coding RNAs. Genome Biol 17:19. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Chu C, Zhang Q, da Rocha S, Flynn RA, Bharadwaj M, Calabrese MJ, Magnuson T, Heard E, Chang HY (2015) Systematic discovery of Xist RNA binding proteins. Cell 161:404–416PubMedPubMedCentralCrossRefGoogle Scholar
  19. Chu H-P, Cifuentes-Rojas C, Kesner B, Aeby E, Lee H, Wei C, Oh H, Boukhali M, Haas W, Lee JT (2017) TERRA RNA antagonizes ATRX and protects telomeres. Cell 170:86–101.e16PubMedPubMedCentralCrossRefGoogle Scholar
  20. Clark MB, Mercer TR, Bussotti G, Leonardi T, Haynes KR, Crawford J, Brunck ME, Cao K-A, Thomas GP, Chen WY et al (2015) Quantitative gene profiling of long noncoding RNAs with targeted RNA sequencing. Nat Methods 12(4):339–342. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Clemson C, McNeil J, Willard H, Lawrence J (1996) XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure. J Cell Biol 132:259–275PubMedCrossRefPubMedCentralGoogle Scholar
  22. Clemson CM, Hutchinson JN, Sara SA, Ensminger AW, Fox AH, Chess A, Lawrence JB (2009) An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of Paraspeckles. Mol Cell 33:717–726PubMedPubMedCentralCrossRefGoogle Scholar
  23. Colognori D, Sunwoo H, Kriz AJ, Wang C-Y, Lee JT (2019) Xist Deletional analysis reveals an interdependency between Xist RNA and Polycomb complexes for spreading along the inactive X. Mol Cell 74:101–117.e10PubMedCrossRefPubMedCentralGoogle Scholar
  24. da Rocha S, Boeva V, Escamilla-Del-Arenal M, Ancelin K, Granier C, Matias N, Sanulli S, Chow J, Schulz E, Picard C et al (2014) Jarid2 is implicated in the initial Xist-induced targeting of PRC2 to the inactive X chromosome. Mol Cell 53:301–316PubMedCrossRefPubMedCentralGoogle Scholar
  25. Davidovich C, Zheng L, Goodrich KJ, Cech TR (2013) Promiscuous RNA binding by Polycomb repressive complex 2. Nat Struct Mol Biol 20:1250–1257PubMedPubMedCentralCrossRefGoogle Scholar
  26. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG et al (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22:1775–1789PubMedPubMedCentralCrossRefGoogle Scholar
  27. Doksani Y, de Lange T (2014) The role of double-strand break repair pathways at functional and dysfunctional telomeres. CSH Perspect Biol 6:a016576Google Scholar
  28. Elbarbary RA, Li W, Tian B, Maquat LE (2013) STAU1 binding 3′ UTR IRAlus complements nuclear retention to protect cells from PKR-mediated translational shutdown. Genes Dev 27:1495–1510PubMedPubMedCentralCrossRefGoogle Scholar
  29. Elguindy MM, Kopp F, Goodarzi M, Rehfeld F, Thomas A, Chang T-C, Mendell JT (2019) PUMILIO, but not RBMX, binding is required for regulation of genomic stability by noncoding RNA NORAD. bioRxiv.
  30. Ellington AD, Szostak JW (1990) In vitro selection of RNA molecules that bind specific ligands. Nature 346:346818a0CrossRefGoogle Scholar
  31. Engreitz JM, Pandya-Jones A, McDonel P, Shishkin A, Sirokman K, Surka C, Kadri S, Xing J, Goren A, Lander ES et al (2013) The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science 341:1237973PubMedPubMedCentralCrossRefGoogle Scholar
  32. Engreitz JM, Sirokman K, McDonel P, Shishkin AA, Surka C, Russell P, Grossman SR, Chow AY, Guttman M, Lander ES (2014) RNA-RNA interactions enable specific targeting of noncoding RNAs to nascent pre-mRNAs and chromatin sites. Cell 159:188–199PubMedPubMedCentralCrossRefGoogle Scholar
  33. Engreitz JM, Haines JE, Perez EM, Munson G, Chen J, Kane M, McDonel PE, Guttman M, Lander ES (2016) Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature 539:452PubMedPubMedCentralCrossRefGoogle Scholar
  34. Gerstberger S, Hafner M, Tuschl T (2014) A census of human RNA-binding proteins. Nat Rev Genet 15:829–845PubMedCrossRefPubMedCentralGoogle Scholar
  35. Gibbons HR, Shaginurova G, Kim LC, Chapman N, Spurlock CF, Aune TM (2018) Divergent lncRNA GATA3-AS1 regulates GATA3 transcription in T-helper 2 cells. Front Immunol 9:2512PubMedPubMedCentralCrossRefGoogle Scholar
  36. Gilbert LA, Horlbeck MA, Adamson B, Villalta JE, Chen Y, Whitehead EH, Guimaraes C, Panning B, Ploegh HL, Bassik MC et al (2014) Genome-scale CRISPR-mediated control of gene repression and activation. Cell 159:647–661PubMedPubMedCentralCrossRefGoogle Scholar
  37. Goff LA, Rinn JL (2015) Linking RNA biology to lncRNAs. Genome Res 25:1456–1465PubMedPubMedCentralCrossRefGoogle Scholar
  38. Gong C, Maquat LE (2011) lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature 470:284PubMedPubMedCentralCrossRefGoogle Scholar
  39. Gong C, Maquat LE (2014) Regulatory non-coding RNAs, methods and protocols. Methods Mol Biol 1206:81–86CrossRefGoogle Scholar
  40. Gong C, Popp M, Maquat LE (2012) Biochemical analysis of long non-coding RNA-containing ribonucleoprotein complexes. Methods 58:88–93PubMedPubMedCentralCrossRefGoogle Scholar
  41. Groff AF, Sanchez-Gomez DB, Soruco M, Gerhardinger C, Barutcu RA, Li E, Elcavage L, Plana O, Sanchez LV, Lee JC et al (2016) In vivo characterization of Linc-p21 reveals functional cis-regulatory DNA elements. Cell Rep 16:2178–2186PubMedPubMedCentralCrossRefGoogle Scholar
  42. Grote P, Herrmann BG (2013) The long non-coding RNA Fendrr links epigenetic control mechanisms to gene regulatory networks in mammalian embryogenesis. RNA Biol 10:1579–1585PubMedPubMedCentralCrossRefGoogle Scholar
  43. Guttman M, Rinn JL (2012) Modular regulatory principles of large non-coding RNAs. Nature 482:339PubMedPubMedCentralCrossRefGoogle Scholar
  44. Guttman M, Garber M, Levin JZ, Donaghey J, Robinson J, Adiconis X, Fan L, Koziol MJ, Gnirke A, Nusbaum C et al (2010) Ab initio reconstruction of cell type–specific transcriptomes in mouse reveals the conserved multi-exonic structure of lincRNAs. Nat Biotechnol 28:503PubMedPubMedCentralCrossRefGoogle Scholar
  45. Hacisuleyman E, Goff LA, Trapnell C, Williams A, Henao-Mejia J, Sun L, McClanahan P, Hendrickson DG, Sauvageau M, Kelley DR et al (2014) Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre. Nat Struct Mol Biol 21:198–206PubMedPubMedCentralCrossRefGoogle Scholar
  46. Hacisuleyman E, Shukla CJ, Weiner CL, Rinn JL (2016) Function and evolution of local repeats in the firre locus. Nat Commun 7:11021PubMedPubMedCentralCrossRefGoogle Scholar
  47. Hafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P, Rothballer A, Ascano M, Jungkamp A-C, Munschauer M et al (2010) Transcriptome-wide identification of RNA-binding protein and MicroRNA target sites by PAR-CLIP. Cell 141:129–141PubMedPubMedCentralCrossRefGoogle Scholar
  48. Hendrickson DG, Kelley DR, Tenen D, Bernstein B, Rinn JL (2016) Widespread RNA binding by chromatin-associated proteins. Genome Biol 17:28CrossRefGoogle Scholar
  49. Hezroni H, Koppstein D, Schwartz MG, Avrutin A, Bartel DP, Ulitsky I (2015) Principles of long noncoding RNA evolution derived from direct comparison of transcriptomes in 17 species. Cell Rep 11:1110–1122PubMedPubMedCentralCrossRefGoogle Scholar
  50. Hirose T, Virnicchi G, Tanigawa A, Naganuma T, Li R, Kimura H, Yokoi T, Nakagawa S, Bénard M, Fox AH et al (2014) NEAT1 long noncoding RNA regulates transcription via protein sequestration within subnuclear bodies. Mol Biol Cell 25:169–183PubMedPubMedCentralCrossRefGoogle Scholar
  51. Hon C-C, Ramilowski JA, Harshbarger J, Bertin N, Rackham OJ, Gough J, Denisenko E, Schmeier S, Poulsen TM, Severin J et al (2017) An atlas of human long non-coding RNAs with accurate 5′ ends. Nature 543:199PubMedPubMedCentralCrossRefGoogle Scholar
  52. Hu W, Yuan B, Flygare J, Lodish HF (2011) Long noncoding RNA-mediated anti-apoptotic activity in murine erythroid terminal differentiation. Genes Dev 25:2573–2578PubMedPubMedCentralCrossRefGoogle Scholar
  53. Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD, Horlings HM, Shah N, Umbricht C, Wang P et al (2011) Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet 43:621PubMedPubMedCentralCrossRefGoogle Scholar
  54. Hutchinson JN, Ensminger AW, Clemson CM, Lynch CR, Lawrence JB, Chess A (2007) A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains. BMC Genomics 8:39PubMedPubMedCentralCrossRefGoogle Scholar
  55. Imamura K, Imamachi N, Akizuki G, Kumakura M, Kawaguchi A, Nagata K, Kato A, Kawaguchi Y, Sato H, Yoneda M et al (2014) Long noncoding RNA NEAT1-dependent SFPQ relocation from promoter region to Paraspeckle mediates IL8 expression upon immune stimuli. Mol Cell 53:393–406PubMedCrossRefPubMedCentralGoogle Scholar
  56. Johnson R, Guigó R (2014) The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs. RNA 20:959–976PubMedPubMedCentralCrossRefGoogle Scholar
  57. Kaewsapsak P, Shechner D, Mallard W, Rinn JL, Ting AY (2017) Live-cell mapping of organelle-associated RNAs via proximity biotinylation combined with protein-RNA crosslinking. Elife 6:e29224PubMedPubMedCentralCrossRefGoogle Scholar
  58. Kapusta A, Kronenberg Z, Lynch VJ, Zhuo X, Ramsay L, Bourque G, Yandell M, Feschotte C (2013) Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs. PLoS Genet 9:e1003470PubMedPubMedCentralCrossRefGoogle Scholar
  59. Kelley D, Rinn J (2012) Transposable elements reveal a stem cell-specific class of long noncoding RNAs. Genome Biol 13:R107PubMedPubMedCentralCrossRefGoogle Scholar
  60. Kelley DR, Hendrickson DG, Tenen D, Rinn JL (2014) Transposable elements modulate human RNA abundance and splicing via specific RNA-protein interactions. Genome Biol 15:537PubMedPubMedCentralCrossRefGoogle Scholar
  61. Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Morales D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A et al (2009) Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A 106:11667–11672PubMedPubMedCentralCrossRefGoogle Scholar
  62. Kim Y, Furic L, DesGroseillers L, Maquat LE (2005) Mammalian Staufen1 recruits Upf1 to specific mRNA 3′UTRs so as to elicit mRNA decay. Cell 120:195–208PubMedCrossRefPubMedCentralGoogle Scholar
  63. Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP (2010) Noncoding RNA Gas5 is a growth arrest– and starvation-associated repressor of the glucocorticoid receptor. Sci Signal 3:ra8PubMedPubMedCentralGoogle Scholar
  64. König J, Zarnack K, Rot G, Curk T, Kayikci M, Zupan B, Turner DJ, Luscombe NM, Ule J (2010) iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat Struct Mol Biol 17:909PubMedPubMedCentralCrossRefGoogle Scholar
  65. Kopp F, Mendell JT (2018) Functional classification and experimental dissection of long noncoding RNAs. Cell 172:393–407PubMedPubMedCentralCrossRefGoogle Scholar
  66. Kotzin JJ, Spencer SP, McCright SJ, Kumar DB, Collet MA, Mowel WK, Elliott EN, Uyar A, Makiya MA, Dunagin MC et al (2016) The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan. Nature 537:239PubMedPubMedCentralCrossRefGoogle Scholar
  67. Latos PA, Pauler FM, Koerner MV, Şenergin BH, Hudson QJ, Stocsits RR, Allhoff W, Stricker SH, Klement RM, Warczok KE et al (2012) Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science 338:1469–1472PubMedCrossRefPubMedCentralGoogle Scholar
  68. Lee JT, Jaenisch R (1997) Long-range cis effects of ectopic X-inactivation centres on a mouse autosome. Nature 386:386275a0Google Scholar
  69. Lee S, Kopp F, Chang T-C, Sataluri A, Chen B, Sivakumar S, Yu H, Xie Y, Mendell JT (2016) Noncoding RNA NORAD regulates genomic stability by sequestering PUMILIO proteins. Cell 164:69–80PubMedCrossRefPubMedCentralGoogle Scholar
  70. Leppek K, Stoecklin G (2014) An optimized streptavidin-binding RNA aptamer for purification of ribonucleoprotein complexes identifies novel ARE-binding proteins. Nucleic Acids Res 42:e13–e13PubMedCrossRefPubMedCentralGoogle Scholar
  71. Leucci E, Vendramin R, Spinazzi M, Laurette P, Fiers M, Wouters J, Radaelli E, Eyckerman S, Leonelli C, Vanderheyden K et al (2016) Melanoma addiction to the long non-coding RNA SAMMSON. Nature 531:518PubMedCrossRefPubMedCentralGoogle Scholar
  72. Li L, Chang HY (2014) Physiological roles of long noncoding RNAs: insight from knockout mice. Trends Cell Biol 24:594–602PubMedPubMedCentralCrossRefGoogle Scholar
  73. Lin A, Li C, Xing Z, Hu Q, Liang K, Han L, Wang C, Hawke DH, Wang S, Zhang Y et al (2016) The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer. Nat Cell Biol 18(2):213–224. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Liu B, Sun L, Liu Q, Gong C, Yao Y, Lv X, Lin L, Yao H, Su F, Li D et al (2015) A cytoplasmic NF-κB interacting long noncoding RNA blocks IκB phosphorylation and suppresses breast Cancer metastasis. Cancer Cell 27:370–381PubMedCrossRefPubMedCentralGoogle Scholar
  75. Liu JS, Horlbeck MA, Cho S, Birk HS, Malatesta M, He D, Attenello FJ, Villalta JE, Cho MY, Chen Y et al (2017) CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells. Science 355:eaah7111CrossRefGoogle Scholar
  76. Lovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J, de Lange T, De S, Petrini JH, Sung PA, Jasin M et al (2012) Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet 8:e1002772PubMedPubMedCentralCrossRefGoogle Scholar
  77. Lubelsky Y, Ulitsky I (2018) Sequences enriched in Alu repeats drive nuclear localization of long RNAs in human cells. Nature 555:107PubMedPubMedCentralCrossRefGoogle Scholar
  78. Maass PG, Rump A, Schulz H, Stricker S, Schulze L, Platzer K, Aydin A, Tinschert S, Goldring MB, Luft FC et al (2012) A misplaced lncRNA causes brachydactyly in humans. J Clin Invest 122:3990–4002PubMedPubMedCentralCrossRefGoogle Scholar
  79. Mao YS, Sunwoo H, Zhang B, Spector DL (2010) Direct visualization of the co-transcriptional assembly of a nuclear body by noncoding RNAs. Nat Cell Biol 13:95PubMedPubMedCentralCrossRefGoogle Scholar
  80. McHugh CA, Russell P, Guttman M (2014) Methods for comprehensive experimental identification of RNA-protein interactions. Genome Biol 15:203PubMedPubMedCentralCrossRefGoogle Scholar
  81. McHugh CA, Chen C-K, Chow A, Surka CF, Tran C, McDonel P, Pandya-Jones A, Blanco M, Burghard C, Moradian A et al (2015) The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3. Nature 521:232PubMedPubMedCentralCrossRefGoogle Scholar
  82. Mélèse T, Xue Z (1995) The nucleolus: an organelle formed by the act of building a ribosome. Curr Opin Cell Biol 7:319–324PubMedCrossRefPubMedCentralGoogle Scholar
  83. Mercer TR, Neph S, Dinger ME, Crawford J, Smith MA, Shearwood A-MJ, Haugen E, Bracken CP, Rackham O, Stamatoyannopoulos JA et al (2011) The human mitochondrial transcriptome. Cell 146:645–658PubMedPubMedCentralCrossRefGoogle Scholar
  84. Mili S, Steitz JA (2004) Evidence for reassociation of RNA-binding proteins after cell lysis: implications for the interpretation of immunoprecipitation analyses. RNA 10:1692–1694PubMedPubMedCentralCrossRefGoogle Scholar
  85. Miller MA, Olivas WM (2011) Roles of Puf proteins in mRNA degradation and translation. Wiley Interdiscip Rev RNA 2:471–492PubMedCrossRefPubMedCentralGoogle Scholar
  86. Misteli T, Cáceres JF, Clement JQ, Krainer AR, Wilkinson MF, Spector DL (1998) Serine phosphorylation of SR proteins is required for their recruitment to sites of transcription in vivo. J Cell Biol 143:297–307PubMedPubMedCentralCrossRefGoogle Scholar
  87. Mondal T, Subhash S, Vaid R, Enroth S, Uday S, Reinius B, Mitra S, Mohammed A, James A, Hoberg E et al (2015) MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA–DNA triplex structures. Nat Commun 6:7743PubMedPubMedCentralCrossRefGoogle Scholar
  88. Monfort A, Di Minin G, Postlmayr A, Freimann R, Arieti F, Thore S, Wutz A (2015) Identification of Spen as a crucial factor for Xist function through forward genetic screening in haploid embryonic stem cells. Cell Rep 12:554–561PubMedPubMedCentralCrossRefGoogle Scholar
  89. Munschauer M, Nguyen CT, Sirokman K, Hartigan CR, Hogstrom L, Engreitz JM, Ulirsch JC, Fulco CP, Subramanian V, Chen J et al (2018) The NORAD lncRNA assembles a topoisomerase complex critical for genome stability. Nature 561:132–136PubMedCrossRefPubMedCentralGoogle Scholar
  90. Naganuma T, Nakagawa S, Tanigawa A, Sasaki YF, Goshima N, Hirose T (2012) Alternative 3′-end processing of long noncoding RNA initiates construction of nuclear paraspeckles. EMBO J 31:4020–4034PubMedPubMedCentralCrossRefGoogle Scholar
  91. Nelson BR, Makarewich CA, Anderson DM, Winders BR, Troupes CD, Wu F, Reese AL, McAnally JR, Chen X, Kavalali ET et al (2016) A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle. Science 351:271–275PubMedPubMedCentralCrossRefGoogle Scholar
  92. Ni T, Yang Y, Hafez D, Yang W, Kiesewetter K, Wakabayashi Y, Ohler U, Peng W, Zhu J (2013) Distinct polyadenylation landscapes of diverse human tissues revealed by a modified PA-seq strategy. BMC Genomics 14:615PubMedPubMedCentralCrossRefGoogle Scholar
  93. Noh J, Kim K, Abdelmohsen K, Yoon J-H, Panda AC, Munk R, Kim J, Curtis J, Moad CA, Wohler CM et al (2016) HuR and GRSF1 modulate the nuclear export and mitochondrial localization of the lncRNA RMRP. Genes Dev 30:1224–1239PubMedPubMedCentralGoogle Scholar
  94. O’Leary V, Ovsepian S, Carrascosa L, Buske F, Radulovic V, Niyazi M, Moertl S, Trau M, Atkinson M, Anastasov N (2015) PARTICLE, a triplex-forming long ncRNA, regulates locus-specific methylation in response to low-dose irradiation. Cell Rep 11:474–485PubMedCrossRefPubMedCentralGoogle Scholar
  95. Paralkar VR, Taborda CC, Huang P, Yao Y, Kossenkov AV, Prasad R, Luan J, Davies J, Hughes JR, Hardison RC et al (2016) Unlinking an lncRNA from its associated cis element. Mol Cell 62:104–110PubMedPubMedCentralCrossRefGoogle Scholar
  96. Parrott AM, Lago H, Adams CJ, Ashcroft AE, Stonehouse NJ, Stockley PG (2000) RNA aptamers for the MS2 bacteriophage coat protein and the wild-type RNA operator have similar solution behaviour. Nucleic Acids Res 28:489–497PubMedPubMedCentralCrossRefGoogle Scholar
  97. Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N (1996) Requirement for Xist in X chromosome inactivation. Nature 379. PubMedCrossRefPubMedCentralGoogle Scholar
  98. Pfeiffer V, Crittin J, Grolimund L, Lingner J (2013) The THO complex component Thp2 counteracts telomeric R-loops and telomere shortening. EMBO J 32:2861–2871PubMedPubMedCentralCrossRefGoogle Scholar
  99. Plath K, Mlynarczyk-Evans S, Nusinow DA, Panning B (2002) Xist RNAand the mechanism of X chromosome inactivation. Annu Rev Genet 36:233–278PubMedCrossRefPubMedCentralGoogle Scholar
  100. Plath K, Fang J, Mlynarczyk-Evans SK, Cao R, Worringer KA, Wang H, de la Cruz CC, Otte AP, Panning B, Zhang Y (2003) Role of histone H3 lysine 27 methylation in X inactivation. Science 300:131–135PubMedCrossRefPubMedCentralGoogle Scholar
  101. Portoso M, Ragazzini R, Brenčič Ž, Moiani A, Michaud A, Vassilev I, Wassef M, Servant N, Sargueil B, Margueron R (2017) PRC2 is dispensable for HOTAIR-mediated transcriptional repression. EMBO J 36:981–994PubMedPubMedCentralCrossRefGoogle Scholar
  102. Postepska-Igielska A, Giwojna A, Gasri-Plotnitsky L, Schmitt N, Dold A, Ginsberg D, Grummt I (2015) LncRNA Khps1 regulates expression of the proto-oncogene SPHK1 via triplex-mediated changes in chromatin structure. Mol Cell 60:626–636PubMedCrossRefPubMedCentralGoogle Scholar
  103. Prasanth KV, Prasanth SG, Xuan Z, Hearn S, Freier SM, Bennett FC, Zhang MQ, Spector DL (2005) Regulating gene expression through RNA nuclear retention. Cell 123:249–263PubMedCrossRefPubMedCentralGoogle Scholar
  104. Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, Lim WA (2013) Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152:1173–1183PubMedPubMedCentralCrossRefGoogle Scholar
  105. Ramanathan M, Majzoub K, Rao DS, Neela PH, Zarnegar BJ, Mondal S, Roth JG, Gai H, Kovalski JR, Siprashvili Z et al (2018) RNA–protein interaction detection in living cells. Nat Methods 15:207PubMedPubMedCentralCrossRefGoogle Scholar
  106. Ramos AD, Andersen RE, Liu S, Nowakowski T, Hong S, Gertz CC, Salinas RD, Zarabi H, Kriegstein AR, Lim DA (2015) The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells. Cell Stem Cell 16:439–447PubMedPubMedCentralCrossRefGoogle Scholar
  107. Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem 81:145–166PubMedCrossRefPubMedCentralGoogle Scholar
  108. Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough HL, Helms JA, Farnham PJ, Segal E et al (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129:1311–1323PubMedPubMedCentralCrossRefGoogle Scholar
  109. Santoro F, Mayer D, Klement RM, Warczok KE, Stukalov A, Barlow DP, Pauler FM (2013) Imprinted Igf2r silencing depends on continuous Airn lncRNA expression and is not restricted to a developmental window. Development 140:1184–1195PubMedCrossRefPubMedCentralGoogle Scholar
  110. Sanz LA, Hartono SR, Lim Y, Steyaert S, Rajpurkar A, Ginno PA, Xu X, Chédin F (2016) Prevalent, dynamic, and conserved R-loop structures associate with specific epigenomic signatures in mammals. Mol Cell 63:167–178PubMedPubMedCentralCrossRefGoogle Scholar
  111. Sasaki YT, Ideue T, Sano M, Mituyama T, Hirose T (2009) MENε/β noncoding RNAs are essential for structural integrity of nuclear paraspeckles. Proc Natl Acad Sci U S A 106:2525–2530PubMedPubMedCentralCrossRefGoogle Scholar
  112. Sauvageau M, Goff LA, Lodato S, Bonev B, Groff AF, Gerhardinger C, Sanchez-Gomez DB, Hacisuleyman E, Li E, Spence M et al (2013) Multiple knockout mouse models reveal lincRNAs are required for life and brain development. Elife 2:e01749PubMedPubMedCentralCrossRefGoogle Scholar
  113. Sentürk Cetin N, Kuo C-C, Ribarska T, Li R, Costa IG, Grummt I (2019) Isolation and genome-wide characterization of cellular DNA:RNA triplex structures. Nucleic Acids Res 47. PubMedPubMedCentralCrossRefGoogle Scholar
  114. Sharma S, Findlay GM, Bandukwala HS, Oberdoerffer S, Baust B, Li Z, Schmidt V, Hogan PG, Sacks DB, Rao A (2011) Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex. Proc Natl Acad Sci U S A 108:11381–11386PubMedPubMedCentralCrossRefGoogle Scholar
  115. Shukla CJ, McCorkindale AL, Gerhardinger C, Korthauer KD, Cabili MN, Shechner D, Irizarry RA, Maass PG, Rinn JL (2018) High-throughput identification of RNA nuclear enrichment sequences. EMBO J 37:e98452PubMedPubMedCentralCrossRefGoogle Scholar
  116. Silva J, Mak W, Zvetkova I, Appanah R, Nesterova TB, Webster Z, Peters A, Jenuwein T, Otte AP, Brockdorff N (2003) Establishment of histone H3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 Polycomb group complexes. Dev Cell 4:481–495PubMedCrossRefPubMedCentralGoogle Scholar
  117. Simon MD, Wang CI, Kharchenko PV, West JA, Chapman BA, Alekseyenko AA, Borowsky ML, Kuroda MI, Kingston RE (2011) The genomic binding sites of a noncoding RNA. Proc Natl Acad Sci U S A 108:20497–20502PubMedPubMedCentralCrossRefGoogle Scholar
  118. Souquere S, Beauclair G, Harper F, Fox A, Pierron G (2010) Highly ordered spatial organization of the structural long noncoding NEAT1 RNAs within Paraspeckle nuclear bodies. Mol Biol Cell 21:4020–4027PubMedPubMedCentralCrossRefGoogle Scholar
  119. Srisawat C, Engelke DR (2001) Streptavidin aptamers: affinity tags for the study of RNAs and ribonucleoproteins. RNA 7:632–641PubMedPubMedCentralCrossRefGoogle Scholar
  120. Sundararaman B, Zhan L, Blue SM, Stanton R, Elkins K, Olson S, Wei X, Van Nostrand EL, Pratt GA, Huelga SC et al (2016) Resources for the comprehensive discovery of functional RNA elements. Mol Cell 61:903–913PubMedPubMedCentralCrossRefGoogle Scholar
  121. Tichon A, Gil N, Lubelsky Y, Solomon T, Lemze D, Itzkovitz S, Stern-Ginossar N, Ulitsky I (2016) A conserved abundant cytoplasmic long noncoding RNA modulates repression by Pumilio proteins in human cells. Nat Commun 7:12209PubMedPubMedCentralCrossRefGoogle Scholar
  122. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett FC, Sharma A, Bubulya PA et al (2010) The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39:925–938PubMedPubMedCentralCrossRefGoogle Scholar
  123. Tsai B, Wang X, Huang L, Waterman ML (2011) Quantitative profiling of in vivo-assembled RNA-protein complexes using a novel integrated proteomic approach. Mol Cell Proteomics 10:M110.007385PubMedPubMedCentralCrossRefGoogle Scholar
  124. Ule J, Jensen KB, Ruggiu M, Mele A, Ule A, Darnell RB (2003) CLIP identifies Nova-regulated RNA networks in the brain. Science 302:1212–1215PubMedPubMedCentralCrossRefGoogle Scholar
  125. Ulitsky I, Bartel DP (2013) lincRNAs: genomics, evolution, and mechanisms. Cell 154:26–46PubMedPubMedCentralCrossRefGoogle Scholar
  126. Vendramin R, Verheyden Y, Ishikawa H, Goedert L, Nicolas E, Saraf K, Armaos A, Ponti R, Izumikawa K, Mestdagh P et al (2018) SAMMSON fosters cancer cell fitness by concertedly enhancing mitochondrial and cytosolic translation. Nat Struct Mol Biol 25:1035–1046PubMedCrossRefPubMedCentralGoogle Scholar
  127. Wang P, Xue Y, Han Y, Lin L, Wu C, Xu S, Jiang Z, Xu J, Liu Q, Cao X (2014) The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation. Science 344:310–313PubMedCrossRefPubMedCentralGoogle Scholar
  128. Wang Z, Zhang X-J, Ji Y-X, Zhang P, Deng K-Q, Gong J, Ren S, Wang X, Chen I, Wang H et al (2016) The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat Med 22:1131–1139PubMedPubMedCentralCrossRefGoogle Scholar
  129. West S, Gromak N, Proudfoot NJ (2004) Human 5′ → 3′ exonuclease Xrn2 promotes transcription termination at co-transcriptional cleavage sites. Nature 432:522PubMedCrossRefPubMedCentralGoogle Scholar
  130. West JA, Davis CP, Sunwoo H, Simon MD, Sadreyev RI, Wang PI, Tolstorukov MY, Kingston RE (2014) The long noncoding RNAs NEAT1 and MALAT1 bind active chromatin sites. Mol Cell 55:791–802PubMedPubMedCentralCrossRefGoogle Scholar
  131. West JA, Mito M, Kurosaka S, Takumi T, Tanegashima C, Chujo T, Yanaka K, Kingston RE, Hirose T, Bond C et al (2016) Structural, super-resolution microscopy analysis of paraspeckle nuclear body organization. J Cell Biol 214:817–830PubMedPubMedCentralCrossRefGoogle Scholar
  132. Willingham A, Orth A, Batalov S, Peters E, Wen B, Aza-Blanc P, Hogenesch J, Schultz P (2005) A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 309:1570–1573PubMedCrossRefPubMedCentralGoogle Scholar
  133. Wutz A, Rasmussen TP, Jaenisch R (2002) Chromosomal silencing and localization are mediated by different domains of Xist RNA. Nat Genet 30:167–174PubMedCrossRefPubMedCentralGoogle Scholar
  134. Yamazaki T, Hirose T (2015) The building process of the functional paraspeckle with long non-coding RNAs. Front Biosci Elite Ed 7:1–41PubMedPubMedCentralGoogle Scholar
  135. Yamazaki T, Souquere S, Chujo T, Kobelke S, Chong Y, Fox AH, Bond CS, Nakagawa S, Pierron G, Hirose T (2018) Functional domains of NEAT1 architectural lncRNA induce Paraspeckle assembly through phase separation. Mol Cell 70:1038–1053.e7PubMedCrossRefPubMedCentralGoogle Scholar
  136. Yan X, Hu Z, Feng Y, Hu X, Yuan J, Zhao SD, Zhang Y, Yang L, Shan W, He Q et al (2015) Comprehensive genomic characterization of long non-coding RNAs across human cancers. Cancer Cell 28:529–540PubMedPubMedCentralCrossRefGoogle Scholar
  137. Zalatan JG, Lee ME, Almeida R, Gilbert LA, Whitehead EH, La Russa M, Tsai JC, Weissman JS, Dueber JE, Qi LS et al (2015) Engineering complex synthetic transcriptional programs with CRISPR RNA scaffolds. Cell 160:339–350PubMedCrossRefPubMedCentralGoogle Scholar
  138. Zhang Z, Carmichael GG (2001) The fate of dsRNA in the nucleus A p54nrb-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs. Cell 106:465–476PubMedCrossRefPubMedCentralGoogle Scholar
  139. Zhang Q, McKenzie NJ, Warneford-Thomson R, Gail EH, Flanigan SF, Owen BM, Lauman R, Levina V, Garcia BA, Schittenhelm RB et al (2019) RNA exploits an exposed regulatory site to inhibit the enzymatic activity of PRC2. Nat Struct Mol Biol 26:237–247PubMedPubMedCentralCrossRefGoogle Scholar
  140. Zhao J, Sun BK, Erwin JA, Song J-J, Lee JT (2008) Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 322:750–756PubMedPubMedCentralCrossRefGoogle Scholar
  141. Zhao J, Ohsumi TK, Kung JT, Ogawa Y, Grau DJ, Sarma K, Song J, Kingston RE, Borowsky M, Lee JT (2010) Genome-wide identification of Polycomb-associated RNAs by RIP-seq. Mol Cell 40:939–953PubMedPubMedCentralCrossRefGoogle Scholar
  142. Zhao Z, Sentürk N, Song C, Grummt I (2018) lncRNA PAPAS tethered to the rDNA enhancer recruits hypophosphorylated CHD4/NuRD to repress rRNA synthesis at elevated temperatures. Genes Dev 32:836–848PubMedPubMedCentralCrossRefGoogle Scholar
  143. Zucchelli S, Fasolo F, Russo R, Cimatti L, Patrucco L, Takahashi H, Jones MH, Santoro C, Sblattero D, Cotella D et al (2015) SINEUPs are modular antisense long non-coding RNAs that increase synthesis of target proteins in cells. Front Cell Neurosci 9:174PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Montreal Clinical Research Institute (IRCM)MontréalCanada
  2. 2.Department of Biochemistry and Molecular MedicineUniversité de MontréalMontréalCanada

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