Skip to main content

Long Noncoding RNAs in Cardiovascular Disease

  • Chapter
  • First Online:
Genetic Causes of Cardiac Disease

Part of the book series: Cardiac and Vascular Biology ((Abbreviated title: Card. vasc. biol.,volume 7))

Abstract

Recent advances in high-throughput sequencing of nucleic acids have led to the fascinating insight that the majority of the human genome is transcribed. This includes tens of thousands of RNAs sized larger than 200 nucleotides that are not translated into proteins and are referred to as long noncoding RNAs (lncRNAs). Until now, only a few of these lncRNAs have been functionally characterized. Here we highlight lncRNAs related to cardiovascular physiology and disease (CVD). We start with an overview of lncRNA classification schemes and of molecular functions of lncRNAs, giving examples of lncRNAs with cardiovascular function in each class. The main focus then is to systematically review 57 lncRNAs implicated in atherosclerosis, myocardial infarction, aortic aneurysm, cardiomyopathy, angiogenesis, arrhythmia, and stroke. We discuss the evidence how these lncRNAs partake in the regulation of cell lineage specification, differentiation potential, cell proliferation, and cell survival in the cardiovascular cell lineages. Specific emphasis is put on recently published lncRNA knockout approaches, and on lncRNAs that have been implicated as important regulators in animal in vivo models of cardiovascular diseases and/or identified in human patient cohorts.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Lee JT, Bartolomei MS. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell. 2013;152:1308–23.

    Article  CAS  PubMed  Google Scholar 

  2. Bertone P, Stolc V, Royce TE, Rozowsky JS, Urban AE, Zhu X, Rinn JL, Tongprasit W, Samanta M, Weissman S, Gerstein M, Snyder M. Global identification of human transcribed sequences with genome tiling arrays. Science. 2004;306:2242–6.

    Article  CAS  PubMed  Google Scholar 

  3. Carninci P, Kasukawa T, Katayama S, Gough J, Frith M, Maeda C, Oyama N, Ravasi R, Lenhard T, Wells B, Kodzius C, Shimokawa R, Bajic K, Brenner VB, Batalov SE, Forrest S, Zavolan AR, Davis M, Wilming MJ, Aidinis LG, Allen V, Ambesi-Impiombato JE, Apweiler A, Aturaliya R, Bailey RN, Bansal TL, Baxter M, Beisel L, Bersano KW, Bono T, Chalk H, Chiu AM, Choudhary KP, Christoffels V, Clutterbuck A, Crowe DR, Dalla ML, Dalrymple E, de Bono BP, Gatta BD, di Bernardo G, Down D, Engstrom T, Fagiolini P, Faulkner M, Fletcher G, Fukushima CF, Furuno T, Futaki M, Gariboldi S, Georgii-Hemming M, Gingeras P, Gojobori TR, Green T, Gustincich RE, Harbers S, Hayashi M, Hensch Y, Hirokawa TK, Hill N, Huminiecki D, Iacono L, Ikeo M, Iwama K, Ishikawa A, Jakt T, Kanapin M, Katoh A, Kawasawa M, Kelso Y, Kitamura J, Kitano H, Kollias H, Krishnan G, Kruger SP, Kummerfeld A, Kurochkin SK, Lareau IV, Lazarevic LF, Lipovich D, Liu L, Liuni J, McWilliam S, Babu SM, Madera M, Marchionni M, Matsuda L, Matsuzawa H, Miki S, Mignone H, Miyake F, Morris S, Mottagui-Tabar K, Mulder S, Nakano N, Nakauchi N, Ng H, Nilsson P, Nishiguchi R, Nishikawa S, et al. The transcriptional landscape of the mammalian genome. Science. 2005;309:1559–63.

    Article  CAS  PubMed  Google Scholar 

  4. Consortium EP, Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE, Kuehn MS, Taylor CM, Neph S, Koch CM, Asthana S, Malhotra A, Adzhubei I, Greenbaum JA, Andrews RM, Flicek P, Boyle PJ, Cao H, Carter NP, Clelland GK, Davis S, Day N, Dhami P, Dillon SC, Dorschner MO, Fiegler H, Giresi PG, Goldy J, Hawrylycz M, Haydock A, Humbert R, James KD, Johnson BE, Johnson EM, Frum TT, Rosenzweig ER, Karnani N, Lee K, Lefebvre GC, Navas PA, Neri F, Parker SC, Sabo PJ, Sandstrom R, Shafer A, Vetrie D, Weaver M, Wilcox S, Yu M, Collins FS, Dekker J, Lieb JD, Tullius TD, Crawford GE, Sunyaev S, Noble WS, Dunham I, Denoeud F, Reymond A, Kapranov P, Rozowsky J, Zheng D, Castelo R, Frankish A, Harrow J, Ghosh S, Sandelin A, Hofacker IL, Baertsch R, Keefe D, Dike S, Cheng J, Hirsch HA, Sekinger EA, Lagarde J, Abril JF, Shahab A, Flamm C, Fried C, Hackermuller J, Hertel J, Lindemeyer M, Missal K, Tanzer A, Washietl S, Korbel J, Emanuelsson O, Pedersen JS, Holroyd N, Taylor R, Swarbreck D, Matthews N, Dickson MC, Thomas DJ, Weirauch MT, et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007;447:799–816.

    Article  CAS  Google Scholar 

  5. Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Roder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K, Bell I, Chakrabortty S, Chen X, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Falconnet E, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Gunawardena H, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Luo OJ, Park E, Persaud K, Preall JB, Ribeca P, Risk B, Robyr D, Sammeth M, Schaffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Ruan X, Hayashizaki Y, Harrow J, Gerstein M, Hubbard T, Reymond A, Antonarakis SE, Hannon G, Giddings MC, Ruan Y, Wold B, Carninci P, Guigo R, Gingeras TR. Landscape of transcription in human cells. Nature. 2012;489:101–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, Ding H, Butty VL, Torrey L, Haas S, Abo R, Tabebordbar M, Lee RT, Burge CB, Boyer LA. Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell. 2013;152:570–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Grote P, Wittler L, Hendrix D, Koch F, Wahrisch S, Beisaw A, Macura K, Blass G, Kellis M, Werber M, Herrmann BG. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev Cell. 2013;24:206–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Anderson KM, Anderson DM, McAnally JR, Shelton JM, Bassel-Duby R, Olson EN. Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development. Nature. 2016;539:433–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Deng C, Li Y, Zhou L, Cho J, Patel B, Terada N, Li Y, Bungert J, Qiu Y, Huang S. HoxBlinc RNA recruits Set1/MLL complexes to activate Hox gene expression patterns and mesoderm lineage development. Cell Rep. 2016;14:103–14.

    Article  CAS  PubMed  Google Scholar 

  10. Broadbent HM, Peden JF, Lorkowski S, Goel A, Ongen H, Green F, Clarke R, Collins R, Franzosi MG, Tognoni G, Seedorf U, Rust S, Eriksson P, Hamsten A, Farrall M, Watkins H, Consortium P. Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Hum Mol Genet. 2008;17:806–14.

    Article  CAS  PubMed  Google Scholar 

  11. Schaefer AS, Richter GM, Groessner-Schreiber B, Noack B, Nothnagel M, El Mokhtari NE, Loos BG, Jepsen S, Schreiber S. Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis. PLoS Genet. 2009;5:e1000378.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Cunnington MS, Santibanez Koref M, Mayosi BM, Burn J, Keavney B. Chromosome 9p21 SNPs associated with multiple disease phenotypes correlate with ANRIL expression. PLoS Genet. 2010;6:e1000899.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Michalik KM, You X, Manavski Y, Doddaballapur A, Zornig M, Braun T, John D, Ponomareva Y, Chen W, Uchida S, Boon RA, Dimmeler S. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ Res. 2014;114:1389–97.

    Article  CAS  PubMed  Google Scholar 

  14. Liu JY, Yao J, Li XM, Song YC, Wang XQ, Li YJ, Yan B, Jiang Q. Pathogenic role of lncRNA-MALAT1 in endothelial cell dysfunction in diabetes mellitus. Cell Death Dis. 2014;5:e1506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Han P, Li W, Lin CH, Yang J, Shang C, Nurnberg ST, Jin KK, Xu W, Lin CY, Lin CJ, Xiong Y, Chien HC, Zhou B, Ashley E, Bernstein D, Chen PS, Chen HS, Quertermous T, Chang CP. A long noncoding RNA protects the heart from pathological hypertrophy. Nature. 2014;514:102–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang Z, Zhang XJ, Ji YX, Zhang P, Deng KQ, Gong J, Ren S, Wang X, Chen I, Wang H, Gao C, Yokota T, Ang YS, Li S, Cass A, Vondriska TM, Li G, Deb A, Srivastava D, Yang HT, Xiao X, Li H, Wang Y. The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat Med. 2016;22:1131–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, Khalil AM, Zuk O, Amit I, Rabani M, Attardi LD, Regev A, Lander ES, Jacks T, Rinn JL. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell. 2010;142:409–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang K, Long B, Zhou LY, Liu F, Zhou QY, Liu CY, Fan YY, Li PF. CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation. Nat Commun. 2014;5:3596.

    Article  PubMed  CAS  Google Scholar 

  19. Ounzain S, Micheletti R, Arnan C, Plaisance I, Cecchi D, Schroen B, Reverter F, Alexanian M, Gonzales C, Ng SY, Bussotti G, Pezzuto I, Notredame C, Heymans S, Guigo R, Johnson R, Pedrazzini T. CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis. J Mol Cell Cardiol. 2015;89:98–112.

    Article  CAS  PubMed  Google Scholar 

  20. Cheng X, Waghulde H, Mell B, Morgan EE, Pruett-Miller SM, Joe B. Positional cloning of quantitative trait nucleotides for blood pressure and cardiac QT-interval by targeted CRISPR/Cas9 editing of a novel long non-coding RNA. PLoS Genet. 2017;13:e1006961.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Loewer S, Cabili MN, Guttman M, Loh YH, Thomas K, Park IH, Garber M, Curran M, Onder T, Agarwal S, Manos PD, Datta S, Lander ES, Schlaeger TM, Daley GQ, Rinn JL. Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet. 2010;42:1113–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Salzman J, Gawad C, Wang PL, Lacayo N, Brown PO. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One. 2012;7:e30733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Burd CE, Jeck WR, Liu Y, Sanoff HK, Wang Z, Sharpless NE. Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk. PLoS Genet. 2010;6:e1001233.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Holdt LM, Stahringer A, Sass K, Pichler G, Kulak NA, Wilfert W, Kohlmaier A, Herbst A, Northoff BH, Nicolaou A, Gabel G, Beutner F, Scholz M, Thiery J, Musunuru K, Krohn K, Mann M, Teupser D. Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nat Commun. 2016;7:12429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, Stadler PF, Hertel J, Hackermuller J, Hofacker IL, Bell I, Cheung E, Drenkow J, Dumais E, Patel S, Helt G, Ganesh M, Ghosh S, Piccolboni A, Sementchenko V, Tammana H, Gingeras TR. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science. 2007;316:1484–8.

    Article  CAS  PubMed  Google Scholar 

  26. Guttman M, Garber M, Levin JZ, Donaghey J, Robinson J, Adiconis X, Fan L, Koziol MJ, Gnirke A, Nusbaum C, Rinn JL, Lander ES, Regev A. Ab initio reconstruction of cell type-specific transcriptomes in mouse reveals the conserved multi-exonic structure of lincRNAs. Nat Biotechnol. 2010;28:503–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cech TR, Steitz JA. The noncoding RNA revolution-trashing old rules to forge new ones. Cell. 2014;157:77–94.

    Article  CAS  PubMed  Google Scholar 

  28. Guttman M, Russell P, Ingolia NT, Weissman JS, Lander ES. Ribosome profiling provides evidence that large noncoding RNAs do not encode proteins. Cell. 2013;154:240–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hon CC, Ramilowski JA, Harshbarger J, Bertin N, Rackham OJ, Gough J, Denisenko E, Schmeier S, Poulsen TM, Severin J, Lizio M, Kawaji H, Kasukawa T, Itoh M, Burroughs AM, Noma S, Djebali S, Alam T, Medvedeva YA, Testa AC, Lipovich L, Yip CW, Abugessaisa I, Mendez M, Hasegawa A, Tang D, Lassmann T, Heutink P, Babina M, Wells CA, Kojima S, Nakamura Y, Suzuki H, Daub CO, de Hoon MJ, Arner E, Hayashizaki Y, Carninci P, Forrest AR. An atlas of human long non-coding RNAs with accurate 5′ ends. Nature. 2017;543:199–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ulitsky I. Evolution to the rescue: using comparative genomics to understand long non-coding RNAs. Nat Rev Genet. 2016;17:601–14.

    Article  CAS  PubMed  Google Scholar 

  31. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, Notredame C, Harrow J, Guigo R. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 2012;22:1775–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A, Regev A, Lander ES, Rinn JL. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A. 2009;106:11667–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. van Heesch S, van Iterson M, Jacobi J, Boymans S, Essers PB, de Bruijn E, Hao W, MacInnes AW, Cuppen E, Simonis M. Extensive localization of long noncoding RNAs to the cytosol and mono- and polyribosomal complexes. Genome Biol. 2014;15:R6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Cabili MN, Dunagin MC, McClanahan PD, Biaesch A, Padovan-Merhar O, Regev A, Rinn JL, Raj A. Localization and abundance analysis of human lncRNAs at single-cell and single-molecule resolution. Genome Biol. 2015;16:20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, Marzluff WF, Sharpless NE. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 2013;19:141–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Clark MB, Johnston RL, Inostroza-Ponta M, Fox AH, Fortini E, Moscato P, Dinger ME, Mattick JS. Genome-wide analysis of long noncoding RNA stability. Genome Res. 2012;22:885–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, Huarte M, Zuk O, Carey BW, Cassady JP, Cabili MN, Jaenisch R, Mikkelsen TS, Jacks T, Hacohen N, Bernstein BE, Kellis M, Regev A, Rinn JL, Lander ES. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 2009;458:223–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Clamp M, Fry B, Kamal M, Xie X, Cuff J, Lin MF, Kellis M, Lindblad-Toh K, Lander ES. Distinguishing protein-coding and noncoding genes in the human genome. Proc Natl Acad Sci U S A. 2007;104:19428–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dinger ME, Pang KC, Mercer TR, Mattick JS. Differentiating protein-coding and noncoding RNA: challenges and ambiguities. PLoS Comput Biol. 2008;4:e1000176.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, Rinn JL. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 2011;25:1915–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ulitsky I, Shkumatava A, Jan CH, Sive H, Bartel DP. Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell. 2011;147:1537–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tilgner H, Knowles DG, Johnson R, Davis CA, Chakrabortty S, Djebali S, Curado J, Snyder M, Gingeras TR, Guigo R. Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional in the human genome but inefficient for lncRNAs. Genome Res. 2012;22:1616–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Engreitz JM, Haines JE, Perez EM, Munson G, Chen J, Kane M, McDonel PE, Guttman M, Lander ES. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature. 2016;539:452–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Huber F, Bunina D, Gupta I, Khmelinskii A, Meurer M, Theer P, Steinmetz LM, Knop M. Protein abundance control by non-coding antisense transcription. Cell Rep. 2016;15:2625–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Joung J, Engreitz JM, Konermann S, Abudayyeh OO, Verdine VK, Aguet F, Gootenberg JS, Sanjana NE, Wright JB, Fulco CP, Tseng YY, Yoon CH, Boehm JS, Lander ES, Zhang F. Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood. Nature. 2017;548(7667):343–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lai F, Gardini A, Zhang A, Shiekhattar R. Integrator mediates the biogenesis of enhancer RNAs. Nature. 2015;525:399–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wilusz JE, JnBaptiste CK, Lu LY, Kuhn CD, Joshua-Tor L, Sharp PA. A triple helix stabilizes the 3′ ends of long noncoding RNAs that lack poly(A) tails. Genes Dev. 2012;26:2392–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schlackow M, Nojima T, Gomes T, Dhir A, Carmo-Fonseca M, Proudfoot NJ. Distinctive patterns of transcription and RNA processing for human lincRNAs. Mol Cell. 2017;65:25–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wilusz JE. Long noncoding RNAs: re-writing dogmas of RNA processing and stability. Biochim Biophys Acta. 2016;1859:128–38.

    Article  CAS  PubMed  Google Scholar 

  50. Yin QF, Yang L, Zhang Y, Xiang JF, Wu YW, Carmichael GG, Chen LL. Long noncoding RNAs with snoRNA ends. Mol Cell. 2012;48:219–30.

    Article  CAS  PubMed  Google Scholar 

  51. Zhang B, Mao YS, Diermeier SD, Novikova IV, Nawrocki EP, Jones TA, Lazar Z, Tung CS, Luo W, Eddy SR, Sanbonmatsu KY, Spector DL. Identification and characterization of a class of MALAT1-like genomic loci. Cell Rep. 2017;19:1723–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Amandio AR, Necsulea A, Joye E, Mascrez B, Duboule D. Hotair is dispensible for mouse development. PLoS Genet. 2016;12:e1006232.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Shan K, Jiang Q, Wang XQ, Wang YN, Yang H, Yao MD, Liu C, Li XM, Yao J, Liu B, Zhang YY, J Y, Yan B. Role of long non-coding RNA-RNCR3 in atherosclerosis-related vascular dysfunction. Cell Death Dis. 2016;7:e2248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Xu C, Zhang Y, Wang Q, Xu Z, Jiang J, Gao Y, Gao M, Kang J, Wu M, Xiong J, Ji K, Yuan W, Wang Y, Liu H. Long non-coding RNA GAS5 controls human embryonic stem cell self-renewal by maintaining NODAL signalling. Nat Commun. 2016;7:13287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zangrando J, Zhang L, Vausort M, Maskali F, Marie PY, Wagner DR, Devaux Y. Identification of candidate long non-coding RNAs in response to myocardial infarction. BMC Genomics. 2014;15:460.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Zhang DD, Wang WT, Xiong J, Xie XM, Cui SS, Zhao ZG, Li MJ, Zhang ZQ, Hao DL, Zhao X, Li YJ, Wang J, Chen HZ, Lv X, Liu DP. Long noncoding RNA LINC00305 promotes inflammation by activating the AHRR-NF-kappaB pathway in human monocytes. Sci Rep. 2017;7:46204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Li Y, Shen S, Ding S, Wang L. LincRNA DYN-LRB2-2 upregulates cholesterol efflux by decreasing TLR2 expression in macrophages. J Cell Biochem. 2018;119:1911–21.

    Article  CAS  PubMed  Google Scholar 

  58. Berretta J, Morillon A. Pervasive transcription constitutes a new level of eukaryotic genome regulation. EMBO Rep. 2009;10:973–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kramer C, Loros JJ, Dunlap JC, Crosthwaite SK. Role for antisense RNA in regulating circadian clock function in Neurospora crassa. Nature. 2003;421:948–52.

    Article  CAS  PubMed  Google Scholar 

  60. Nagano T, Mitchell JA, Sanz LA, Pauler FM, Ferguson-Smith AC, Feil R, Fraser P. The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science. 2008;322:1717–20.

    Article  CAS  PubMed  Google Scholar 

  61. Camblong J, Iglesias N, Fickentscher C, Dieppois G, Stutz F. Antisense RNA stabilization induces transcriptional gene silencing via histone deacetylation in S. cerevisiae. Cell. 2007;131:706–17.

    Article  CAS  PubMed  Google Scholar 

  62. Prescott EM, Proudfoot NJ. Transcriptional collision between convergent genes in budding yeast. Proc Natl Acad Sci U S A. 2002;99:8796–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hobson DJ, Wei W, Steinmetz LM, Svejstrup JQ. RNA polymerase II collision interrupts convergent transcription. Mol Cell. 2012;48:365–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lee JT, Lu N. Targeted mutagenesis of Tsix leads to nonrandom X inactivation. Cell. 1999;99:47–57.

    Article  CAS  PubMed  Google Scholar 

  65. Sado T, Hoki Y, Sasaki H. Tsix silences Xist through modification of chromatin structure. Dev Cell. 2005;9:159–65.

    Article  CAS  PubMed  Google Scholar 

  66. Pasmant E, Laurendeau I, Heron D, Vidaud M, Vidaud D, Bieche I. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Res. 2007;67:3963–9.

    Article  CAS  PubMed  Google Scholar 

  67. Bell RD, Long X, Lin M, Bergmann JH, Nanda V, Cowan SL, Zhou Q, Han Y, Spector DL, Zheng D, Miano JM. Identification and initial functional characterization of a human vascular cell-enriched long noncoding RNA. Arterioscler Thromb Vasc Biol. 2014;34:1249–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zong X, Nakagawa S, Freier SM, Fei J, Ha T, Prasanth SG, Prasanth KV. Natural antisense RNA promotes 3′ end processing and maturation of MALAT1 lncRNA. Nucleic Acids Res. 2016;44:2898–908.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Leisegang MS, Fork C, Josipovic I, Richter F, Preussner J, Hu J, Miller MJ, Epah JN, Hofmann P, Gunther S, Moll F, Valasarajan C, Heidler J, Ponomareva Y, Freiman TM, Maegdefessel L, Plate KH, Mittelbronn M, Uchida S, Kunne C, Stellos K, Schermuly RT, Weissmann N, Devraj K, Wittig I, Boon RA, Dimmeler S, Pullamsetti SS, Looso M, Miller FJ, Brandes RP. Long noncoding RNA MANTIS facilitates endothelial angiogenic function. Circulation. 2017;136(1):65–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Huang C, Hu YW, Zhao JJ, Ma X, Zhang Y, Guo FX, Kang CM, Lu JB, Xiu JC, Sha YH, Gao JJ, Wang YC, Li P, Xu BM, Zheng L, Wang Q. Long noncoding RNA HOXC-AS1 suppresses Ox-LDL-induced cholesterol accumulation through promoting HOXC6 expression in THP-1 macrophages. DNA Cell Biol. 2016;35:722–9.

    Article  CAS  PubMed  Google Scholar 

  71. Zhao Y, Feng G, Wang Y, Yue Y, Zhao W. Regulation of apoptosis by long non-coding RNA HIF1A-AS1 in VSMCs: implications for TAA pathogenesis. Int J Clin Exp Pathol. 2014;7:7643–52.

    PubMed  PubMed Central  Google Scholar 

  72. Lee MP, DeBaun MR, Mitsuya K, Galonek HL, Brandenburg S, Oshimura M, Feinberg AP. Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. Proc Natl Acad Sci U S A. 1999;96:5203–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mehta SL, Kim T, Vemuganti R. Long noncoding RNA FosDT promotes ischemic brain injury by interacting with REST-associated chromatin-modifying proteins. J Neurosci. 2015;35:16443–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Preker P, Nielsen J, Kammler S, Lykke-Andersen S, Christensen MS, Mapendano CK, Schierup MH, Jensen TH. RNA exosome depletion reveals transcription upstream of active human promoters. Science. 2008;322:1851–4.

    Article  CAS  PubMed  Google Scholar 

  75. Ntini E, Jarvelin AI, Bornholdt J, Chen Y, Boyd M, Jorgensen M, Andersson R, Hoof I, Schein A, Andersen PR, Andersen PK, Preker P, Valen E, Zhao X, Pelechano V, Steinmetz LM, Sandelin A, Jensen TH. Polyadenylation site-induced decay of upstream transcripts enforces promoter directionality. Nat Struct Mol Biol. 2013;20:923–8.

    Article  CAS  PubMed  Google Scholar 

  76. Almada AE, Wu X, Kriz AJ, Burge CB, Sharp PA. Promoter directionality is controlled by U1 snRNP and polyadenylation signals. Nature. 2013;499:360–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Neil H, Malabat C, d’Aubenton-Carafa Y, Xu Z, Steinmetz LM, Jacquier A. Widespread bidirectional promoters are the major source of cryptic transcripts in yeast. Nature. 2009;457:1038–42.

    Article  CAS  PubMed  Google Scholar 

  78. Schulz D, Schwalb B, Kiesel A, Baejen C, Torkler P, Gagneur J, Soeding J, Cramer P. Transcriptome surveillance by selective termination of noncoding RNA synthesis. Cell. 2013;155:1075–87.

    Article  CAS  PubMed  Google Scholar 

  79. Xu Z, Wei W, Gagneur J, Perocchi F, Clauder-Munster S, Camblong J, Guffanti E, Stutz F, Huber W, Steinmetz LM. Bidirectional promoters generate pervasive transcription in yeast. Nature. 2009;457:1033–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Pelechano V, Steinmetz LM. Gene regulation by antisense transcription. Nat Rev Genet. 2013;14:880–93.

    Article  CAS  PubMed  Google Scholar 

  81. Kim TK, Hemberg M, Gray JM, Costa AM, Bear DM, Wu J, Harmin DA, Laptewicz M, Barbara-Haley K, Kuersten S, Markenscoff-Papadimitriou E, Kuhl D, Bito H, Worley PF, Kreiman G, Greenberg ME. Widespread transcription at neuronal activity-regulated enhancers. Nature. 2010;465:182–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang D, Garcia-Bassets I, Benner C, Li W, Su X, Zhou Y, Qiu J, Liu W, Kaikkonen MU, Ohgi KA, Glass CK, Rosenfeld MG, Fu XD. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature. 2011;474:390–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Li W, Notani D, Ma Q, Tanasa B, Nunez E, Chen AY, Merkurjev D, Zhang J, Ohgi K, Song X, Oh S, Kim HS, Glass CK, Rosenfeld MG. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature. 2013;498:516–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Puc J, Kozbial P, Li W, Tan Y, Liu Z, Suter T, Ohgi KA, Zhang J, Aggarwal AK, Rosenfeld MG. Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell. 2015;160:367–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Li W, Notani D, Rosenfeld MG. Enhancers as non-coding RNA transcription units: recent insights and future perspectives. Nat Rev Genet. 2016;17:207–23.

    Article  CAS  PubMed  Google Scholar 

  86. Shiraki T, Kondo S, Katayama S, Waki K, Kasukawa T, Kawaji H, Kodzius R, Watahiki A, Nakamura M, Arakawa T, Fukuda S, Sasaki D, Podhajska A, Harbers M, Kawai J, Carninci P, Hayashizaki Y. Cap analysis gene expression for high-throughput analysis of transcriptional starting point and identification of promoter usage. Proc Natl Acad Sci U S A. 2003;100:15776–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Murakawa Y, Yoshihara M, Kawaji H, Nishikawa M, Zayed H, Suzuki H, Fantom C, Hayashizaki Y. Enhanced Identification of Transcriptional Enhancers Provides Mechanistic Insights into Diseases. Trends Genet. 2016;32:76–88.

    Article  CAS  PubMed  Google Scholar 

  88. Kwak H, Fuda NJ, Core LJ, Lis JT. Precise maps of RNA polymerase reveal how promoters direct initiation and pausing. Science. 2013;339:950–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Orom UA, Derrien T, Beringer M, Gumireddy K, Gardini A, Bussotti G, Lai F, Zytnicki M, Notredame C, Huang Q, Guigo R, Shiekhattar R. Long noncoding RNAs with enhancer-like function in human cells. Cell. 2010;143:46–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Vucicevic D, Corradin O, Ntini E, Scacheri PC, Orom UA. Long ncRNA expression associates with tissue-specific enhancers. Cell Cycle. 2015;14:253–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Micheletti R, Plaisance I, Abraham BJ, Sarre A, Ting CC, Alexanian M, Maric D, Maison D, Nemir M, Young RA, Schroen B, Gonzalez A, Ounzain S, Pedrazzini T. The long noncoding RNA Wisper controls cardiac fibrosis and remodeling. Sci Transl Med. 2017;9

    Google Scholar 

  92. Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA, Wysocka J, Lei M, Dekker J, Helms JA, Chang HY. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011;472:120–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Maamar H, Cabili MN, Rinn J, Raj A. linc-HOXA1 is a noncoding RNA that represses Hoxa1 transcription in cis. Genes Dev. 2013;27:1260–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ballantyne MD, Pinel K, Dakin R, Vesey AT, Diver L, Mackenzie R, Garcia R, Welsh P, Sattar N, Hamilton G, Joshi N, Dweck MR, Miano JM, McBride MW, Newby DE, McDonald RA, Baker AH. Smooth muscle enriched long noncoding RNA (SMILR) regulates cell proliferation. Circulation. 2016;133:2050–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Nakaya HI, Amaral PP, Louro R, Lopes A, Fachel AA, Moreira YB, El-Jundi TA, da Silva AM, Reis EM, Verjovski-Almeida S. Genome mapping and expression analyses of human intronic noncoding RNAs reveal tissue-specific patterns and enrichment in genes related to regulation of transcription. Genome Biol. 2007;8:R43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Gardner EJ, Nizami ZF, Talbot CC Jr, Gall JG. Stable intronic sequence RNA (sisRNA), a new class of noncoding RNA from the oocyte nucleus of Xenopus tropicalis. Genes Dev. 2012;26:2550–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Pek JW, Osman I, Tay ML, Zheng RT. Stable intronic sequence RNAs have possible regulatory roles in Drosophila melanogaster. J Cell Biol. 2015;211:243–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Duret L, Chureau C, Samain S, Weissenbach J, Avner P. The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene. Science. 2006;312:1653–5.

    Article  CAS  PubMed  Google Scholar 

  99. Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010;465:1033–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Guo JU, Agarwal V, Guo H, Bartel DP. Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 2014;15:409.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Salzman J, Chen RE, Olsen MN, Wang PL, Brown PO. Cell-type specific features of circular RNA expression. PLoS Genet. 2013;9:e1003777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Rybak-Wolf A, Stottmeister C, Glazar P, Jens M, Pino N, Giusti S, Hanan M, Behm M, Bartok O, Ashwal-Fluss R, Herzog M, Schreyer L, Papavasileiou P, Ivanov A, Ohman M, Refojo D, Kadener S, Rajewsky N. Circular RNAs in the mammalian brain are highly abundant. Conserved, and Dynamically Expressed, Mol Cell. 2015;58:870–85.

    Article  CAS  PubMed  Google Scholar 

  103. Barrett SP, Salzman J. Circular RNAs: analysis, expression and potential functions. Development. 2016;143:1838–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Holdt LM, Kohlmaier A, Teupser D. Molecular roles and function of circular RNAs in eukaryotic cells. Cell Mol Life Sci. 2018;75(6):1071–98.

    Article  CAS  PubMed  Google Scholar 

  105. Wang K, Long B, Liu F, Wang JX, Liu CY, Zhao B, Zhou LY, Sun T, Wang M, Yu T, Gong Y, Liu J, Dong YH, Li N, Li PF. A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223. Eur Heart J. 2016;37:2602–11.

    Article  CAS  PubMed  Google Scholar 

  106. Wang K, Gan TY, Li N, Liu CY, Zhou LY, Gao JN, Chen C, Yan KW, Ponnusamy M, Zhang YH, Li PF. Circular RNA mediates cardiomyocyte death via miRNA-dependent upregulation of MTP18 expression. Cell Death Differ. 2017;24:1111–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kondo T, Hashimoto Y, Kato K, Inagaki S, Hayashi S, Kageyama Y. Small peptide regulators of actin-based cell morphogenesis encoded by a polycistronic mRNA. Nat Cell Biol. 2007;9:660–5.

    Article  CAS  PubMed  Google Scholar 

  108. Hanyu-Nakamura K, Sonobe-Nojima H, Tanigawa A, Lasko P, Nakamura A. Drosophila Pgc protein inhibits P-TEFb recruitment to chromatin in primordial germ cells. Nature. 2008;451:730–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kondo T, Plaza S, Zanet J, Benrabah E, Valenti P, Hashimoto Y, Kobayashi S, Payre F, Kageyama Y. Small peptides switch the transcriptional activity of Shavenbaby during Drosophila embryogenesis. Science. 2010;329:336–9.

    Article  CAS  PubMed  Google Scholar 

  110. Magny EG, Pueyo JI, Pearl FM, Cespedes MA, Niven JE, Bishop SA, Couso JP. Conserved regulation of cardiac calcium uptake by peptides encoded in small open reading frames. Science. 2013;341:1116–20.

    Article  CAS  PubMed  Google Scholar 

  111. Pauli A, Norris ML, Valen E, Chew GL, Gagnon JA, Zimmerman S, Mitchell A, Ma J, Dubrulle J, Reyon D, Tsai SQ, Joung JK, Saghatelian A, Schier AF. Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science. 2014;343:1248636.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Anderson DM, Anderson KM, Chang CL, Makarewich CA, Nelson BR, McAnally JR, Kasaragod P, Shelton JM, Liou J, Bassel-Duby R, Olson EN. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell. 2015;160:595–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Rohrig H, Schmidt J, Miklashevichs E, Schell J, John M. Soybean ENOD40 encodes two peptides that bind to sucrose synthase. Proc Natl Acad Sci U S A. 2002;99:1915–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Pauli A, Valen E, Schier AF. Identifying (non-)coding RNAs and small peptides: challenges and opportunities. BioEssays. 2015;37:103–12.

    Article  CAS  PubMed  Google Scholar 

  115. Slavoff SA, Mitchell AJ, Schwaid AG, Cabili MN, Ma J, Levin JZ, Karger AD, Budnik BA, Rinn JL, Saghatelian A. Peptidomic discovery of short open reading frame-encoded peptides in human cells. Nat Chem Biol. 2013;9:59–64.

    Article  CAS  PubMed  Google Scholar 

  116. Nelson BR, Makarewich CA, Anderson DM, Winders BR, Troupes CD, Wu F, Reese AL, McAnally JR, Chen X, Kavalali ET, Cannon SC, Houser SR, Bassel-Duby R, Olson EN. A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle. Science. 2016;351:271–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Monfort A, Di Minin G, Postlmayr A, Freimann R, Arieti F, Thore S, Wutz A. Identification of Spen as a crucial factor for Xist function through forward genetic screening in haploid embryonic stem cells. Cell Rep. 2015;12:554–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kurian L, Aguirre A, Sancho-Martinez I, Benner C, Hishida T, Nguyen TB, Reddy P, Nivet E, Krause MN, Nelles DA, Esteban CR, Campistol JM, Yeo GW, Belmonte JCI. Identification of novel long noncoding RNAs underlying vertebrate cardiovascular development. Circulation. 2015;131:1278–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Jiang W, Liu Y, Liu R, Zhang K, Zhang Y. The lncRNA DEANR1 facilitates human endoderm differentiation by activating FOXA2 expression. Cell Rep. 2015;11:137–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Puri MC, Rossant J, Alitalo K, Bernstein A, Partanen J. The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. EMBO J. 1995;14:5884–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Li K, Blum Y, Verma A, Liu Z, Pramanik K, Leigh NR, Chun CZ, Samant GV, Zhao B, Garnaas MK, Horswill MA, Stanhope SA, North PE, Miao RQ, Wilkinson GA, Affolter M, Ramchandran R. A noncoding antisense RNA in tie-1 locus regulates tie-1 function in vivo. Blood. 2010;115:133–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Limaye N, Wouters V, Uebelhoer M, Tuominen M, Wirkkala R, Mulliken JB, Eklund L, Boon LM, Vikkula M. Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat Genet. 2009;41:118–24.

    Article  CAS  PubMed  Google Scholar 

  123. Yang L, Kirby JE, Sunwoo H, Lee JT. Female mice lacking Xist RNA show partial dosage compensation and survive to term. Genes Dev. 2016;30:1747–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT, Lee JT. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell. 2013;152:727–42.

    Article  CAS  PubMed  Google Scholar 

  125. Savarese F, Flahndorfer K, Jaenisch R, Busslinger M, Wutz A. Hematopoietic precursor cells transiently reestablish permissiveness for X inactivation. Mol Cell Biol. 2006;26:7167–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Zhang B, Arun G, Mao YS, Lazar Z, Hung G, Bhattacharjee G, Xiao X, Booth CJ, Wu J, Zhang C, Spector DL. The lncRNA Malat1 is dispensable for mouse development but its transcription plays a cis-regulatory role in the adult. Cell Rep. 2012;2:111–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Nakagawa S, Ip JY, Shioi G, Tripathi V, Zong X, Hirose T, Prasanth KV. Malat1 is not an essential component of nuclear speckles in mice. RNA. 2012;18:1487–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Eissmann M, Gutschner T, Hammerle M, Gunther S, Caudron-Herger M, Gross M, Schirmacher P, Rippe K, Braun T, Zornig M, Diederichs S. Loss of the abundant nuclear non-coding RNA MALAT1 is compatible with life and development. RNA Biol. 2012;9:1076–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Holdt LM, Beutner F, Scholz M, Gielen S, Gabel G, Bergert H, Schuler G, Thiery J, Teupser D. ANRIL expression is associated with atherosclerosis risk at chromosome 9p21. Arterioscler Thromb Vasc Biol. 2010;30:620–7.

    Article  CAS  PubMed  Google Scholar 

  130. Cooper JD, Walker NM, Smyth DJ, Downes K, Healy BC, Todd JA, Type IDGC. Follow-up of 1715 SNPs from the Wellcome Trust Case Control Consortium genome-wide association study in type I diabetes families. Genes Immun. 2009;10(Suppl 1):S85–94.

    Article  PubMed  PubMed Central  Google Scholar 

  131. McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR, Hinds DA, Pennacchio LA, Tybjaerg-Hansen A, Folsom AR, Boerwinkle E, Hobbs HH, Cohen JC. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007;316:1488–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Liu Y, Sanoff HK, Cho H, Burd CE, Torrice C, Mohlke KL, Ibrahim JG, Thomas NE, Sharpless NE. INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis. PLoS One. 2009;4:e5027.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Jarinova O, Stewart AF, Roberts R, Wells G, Lau P, Naing T, Buerki C, McLean BW, Cook RC, Parker JS, McPherson R. Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arterioscler Thromb Vasc Biol. 2009;29:1671–7.

    Article  CAS  PubMed  Google Scholar 

  134. Holdt LM, Teupser D. Recent studies of the human chromosome 9p21 locus, which is associated with atherosclerosis in human populations. Arterioscler Thromb Vasc Biol. 2012;32:196–206.

    Article  CAS  PubMed  Google Scholar 

  135. Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A, Jonasdottir A, Sigurdsson A, Baker A, Palsson A, Masson G, Gudbjartsson DF, Magnusson KP, Andersen K, Levey AI, Backman VM, Matthiasdottir S, Jonsdottir T, Palsson S, Einarsdottir H, Gunnarsdottir S, Gylfason A, Vaccarino V, Hooper WC, Reilly MP, Granger CB, Austin H, Rader DJ, Shah SH, Quyyumi AA, Gulcher JR, Thorgeirsson G, Thorsteinsdottir U, Kong A, Stefansson K. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007;316:1491–3.

    Article  CAS  PubMed  Google Scholar 

  136. Helgadottir A, Thorleifsson G, Magnusson KP, Gretarsdottir S, Steinthorsdottir V, Manolescu A, Jones GT, Rinkel GJ, Blankensteijn JD, Ronkainen A, Jaaskelainen JE, Kyo Y, Lenk GM, Sakalihasan N, Kostulas K, Gottsater A, Flex A, Stefansson H, Hansen T, Andersen G, Weinsheimer S, Borch-Johnsen K, Jorgensen T, Shah SH, Quyyumi AA, Granger CB, Reilly MP, Austin H, Levey AI, Vaccarino V, Palsdottir E, Walters GB, Jonsdottir T, Snorradottir S, Magnusdottir D, Gudmundsson G, Ferrell RE, Sveinbjornsdottir S, Hernesniemi J, Niemela M, Limet R, Andersen K, Sigurdsson G, Benediktsson R, Verhoeven EL, Teijink JA, Grobbee DE, Rader DJ, Collier DA, Pedersen O, Pola R, Hillert J, Lindblad B, Valdimarsson EM, Magnadottir HB, Wijmenga C, Tromp G, Baas AF, Ruigrok YM, van Rij AM, Kuivaniemi H, Powell JT, Matthiasson SE, Gulcher JR, Thorgeirsson G, Kong A, Thorsteinsdottir U, Stefansson K. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008;40:217–24.

    Article  CAS  PubMed  Google Scholar 

  137. Matarin M, BrownWM, Singleton A, Hardy JA, Meschia JF, ISGS Investigators. Whole genome analyses suggest ischemic stroke and heart disease share an association with polymorphisms on chromosome 9p21. Stroke. 2008;39:1586–9.

    Article  CAS  Google Scholar 

  138. Smith JG, Melander O, Lovkvist H, Hedblad B, Engstrom G, Nilsson P, Carlson J, Berglund G, Norrving B, Lindgren A. Common genetic variants on chromosome 9p21 confers risk of ischemic stroke: a large-scale genetic association study. Circ Cardiovasc Genet. 2009;2:159–64.

    Article  CAS  PubMed  Google Scholar 

  139. Wahlstrand B, Orho-Melander M, Delling L, Kjeldsen S, Narkiewicz K, Almgren P, Hedner T, Melander O. The myocardial infarction associated CDKN2A/CDKN2B locus on chromosome 9p21 is associated with stroke independently of coronary events in patients with hypertension. J Hypertens. 2009;27:769–73.

    Article  CAS  PubMed  Google Scholar 

  140. Anderson CD, Biffi A, Rost NS, Cortellini L, Furie KL, Rosand J. Chromosome 9p21 in ischemic stroke: population structure and meta-analysis. Stroke. 2010;41:1123–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Zhang W, Chen Y, Liu P, Chen J, Song L, Tang Y, Wang Y, Liu J, Hu FB, Hui R. Variants on chromosome 9p21.3 correlated with ANRIL expression contribute to stroke risk and recurrence in a large prospective stroke population. Stroke. 2012;43:14–21.

    Article  PubMed  CAS  Google Scholar 

  142. Bai Y, Nie S, Jiang G, Zhou Y, Zhou M, Zhao Y, Li S, Wang F, Lv Q, Huang Y, Yang Q, Li Q, Li Y, Xia Y, Liu Y, Liu J, Qian J, Li B, Wu G, Wu Y, Wang B, Cheng X, Yang Y, Ke T, Li H, Ren X, Ma X, Liao Y, Xu C, Tu X, Wang QK. Regulation of CARD8 expression by ANRIL and association of CARD8 single nucleotide polymorphism rs2043211 (p.C10X) with ischemic stroke. Stroke. 2014;45:383–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Zhang B, Wang D, Ji TF, Shi L, Yu JL. Overexpression of lncRNA ANRIL up-regulates VEGF expression and promotes angiogenesis of diabetes mellitus combined with cerebral infarction by activating NF-kappaB signaling pathway in a rat model. Oncotarget. 2017;8:17347–59.

    PubMed  Google Scholar 

  144. Chen L, Yao H, Hui JY, Ding SH, Fan YL, Pan YH, Chen KH, Wan JQ, Jiang JY. Global transcriptomic study of atherosclerosis development in rats. Gene. 2016;592:43–8.

    Article  CAS  PubMed  Google Scholar 

  145. Arslan S, Berkan O, Lalem T, Ozbilum N, Goksel S, Korkmaz O, Cetin N, Devaux Y, Cardiolinc Network. Long non-coding RNAs in the atherosclerotic plaque. Atherosclerosis. 2017;266:176–81.

    Article  CAS  Google Scholar 

  146. Qu X, Du Y, Shu Y, Gao M, Sun F, Luo S, Yang T, Zhan L, Yuan Y, Chu W, Pan Z, Wang Z, Yang B, Lu Y. MIAT Is a Pro-fibrotic Long Non-coding RNA Governing Cardiac Fibrosis in Post-infarct Myocardium. Sci Rep. 2017;7:42657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Frade AF, Laugier L, Ferreira LR, Baron MA, Benvenuti LA, Teixeira PC, Navarro IC, Cabantous S, Ferreira FM, da Silva Candido D, Gaiotto FA, Bacal F, Pomerantzeff P, Santos RH, Kalil J, Cunha-Neto E, Chevillard C. Myocardial infarction-associated transcript, a long noncoding RNA. Is Overexpressed During Dilated Cardiomyopathy Due to Chronic Chagas Disease, J Infect Dis. 2016;214:161–5.

    CAS  PubMed  Google Scholar 

  148. Yan B, Yao J, Liu JY, Li XM, Wang XQ, Li YJ, Tao ZF, Song YC, Chen Q, Jiang Q. lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA. Circ Res. 2015;116:1143–56.

    Article  CAS  PubMed  Google Scholar 

  149. Gao W, Zhu M, Wang H, Zhao S, Zhao D, Yang Y, Wang ZM, Wang F, Yang ZJ, Lu X, Wang LS. Association of polymorphisms in long non-coding RNA H19 with coronary artery disease risk in a Chinese population. Mutat Res. 2015;772:15–22.

    Article  CAS  PubMed  Google Scholar 

  150. Zhang Z, Gao W, Long QQ, Zhang J, Li YF, Liu DC, Yan JJ, Yang ZJ, Wang LS. Increased plasma levels of lncRNA H19 and LIPCAR are associated with increased risk of coronary artery disease in a Chinese population. Sci Rep. 2017;7:7491.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Han Y, Ma J, Wang J, Wang L. Silencing of H19 inhibits the adipogenesis and inflammation response in ox-LDL-treated Raw264.7 cells by up-regulating miR-130b. Mol Immunol. 2017;93:107–14.

    Article  PubMed  CAS  Google Scholar 

  152. Hadji F, Boulanger MC, Guay SP, Gaudreault N, Amellah S, Mkannez G, Bouchareb R, Marchand JT, Nsaibia MJ, Guauque-Olarte S, Pibarot P, Bouchard L, Bosse Y, Mathieu P. Altered DNA methylation of long noncoding RNA H19 in calcific aortic valve disease promotes mineralization by silencing NOTCH1. Circulation. 2016;134:1848–62.

    Article  CAS  PubMed  Google Scholar 

  153. Wang J, Zhao H, Fan Z, Li G, Ma Q, Tao Z, Wang R, Feng J, Luo Y. Long noncoding RNA H19 promotes neuroinflammation in ischemic stroke by driving histone deacetylase 1-dependent M1 microglial polarization. Stroke. 2017;48:2211–21.

    Article  CAS  PubMed  Google Scholar 

  154. Wang J, Cao B, Han D, Sun M, Feng J. Long non-coding RNA H19 induces cerebral ischemia reperfusion injury via activation of autophagy. Aging Dis. 2017;8:71–84.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Vigetti D, Deleonibus S, Moretto P, Bowen T, Fischer JW, Grandoch M, Oberhuber A, Love DC, Hanover JA, Cinquetti R, Karousou E, Viola M, D'Angelo ML, Hascall VC, De Luca G, Passi A. Natural antisense transcript for hyaluronan synthase 2 (HAS2-AS1) induces transcription of HAS2 via protein O-GlcNAcylation. J Biol Chem. 2014;289:28816–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Liao B, Chen R, Lin F, Mai A, Chen J, Li H, Xu Z, Dong S. Long noncoding RNA HOTTIP promotes endothelial cell proliferation and migration via activation of the Wnt/beta-catenin pathway. J Cell Biochem. 2018;119(3):2797–805.

    Article  CAS  PubMed  Google Scholar 

  157. Hu YW, Yang JY, Ma X, Chen ZP, Hu YR, Zhao JY, Li SF, Qiu YR, Lu JB, Wang YC, Gao JJ, Sha YH, Zheng L, Wang Q. A lincRNA-DYNLRB2-2/GPR119/GLP-1R/ABCA1-dependent signal transduction pathway is essential for the regulation of cholesterol homeostasis. J Lipid Res. 2014;55:681–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Tang SS, Cheng J, Cai MY, Yang XL, Liu XG, Zheng BY, Xiong XD. Association of lincRNA-p21 haplotype with coronary artery disease in a Chinese han population. Dis Markers. 2016;2016:9109743.

    PubMed  PubMed Central  Google Scholar 

  159. Wu G, Cai J, Han Y, Chen J, Huang ZP, Chen C, Cai Y, Huang H, Yang Y, Liu Y, Xu Z, He D, Zhang X, Hu X, Pinello L, Zhong D, He F, Yuan GC, Wang DZ, Zeng C. LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity. Circulation. 2014;130:1452–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Wu Z, He Y, Li D, Fang X, Shang T, Zhang H, Zheng X. Long noncoding RNA MEG3 suppressed endothelial cell proliferation and migration through regulating miR-21. Am J Transl Res. 2017;9:3326–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Piccoli MT, Gupta SK, Viereck J, Foinquinos A, Samolovac S, Kramer FL, Garg A, Remke J, Zimmer K, Batkai S, Thum T. Inhibition of the cardiac fibroblast-enriched lncRNA Meg3 prevents cardiac fibrosis and diastolic dysfunction. Circ Res. 2017;121:575–83.

    Article  CAS  PubMed  Google Scholar 

  162. Yan H, Yuan J, Gao L, Rao J, Hu J. Long noncoding RNA MEG3 activation of p53 mediates ischemic neuronal death in stroke. Neuroscience. 2016;337:191–9.

    Article  CAS  PubMed  Google Scholar 

  163. Shahmoradi N, Nasiri M, Kamfiroozi H, Kheiry MA. Association of the rs555172 polymorphism in SENCR long non-coding RNA and atherosclerotic coronary artery disease. J Cardiovasc Thorac Res. 2017;9:170–4.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Boulberdaa M, Scott E, Ballantyne M, Garcia R, Descamps B, Angelini GD, Brittan M, Hunter A, McBride M, McClure J, Miano JM, Emanueli C, Mills NL, Mountford JC, Baker AH. A role for the long noncoding RNA SENCR in commitment and function of endothelial cells. Mol Ther. 2016;24:978–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Chen C, Cheng G, Yang X, Li C, Shi R, Zhao N. Tanshinol suppresses endothelial cells apoptosis in mice with atherosclerosis via lncRNA TUG1 up-regulating the expression of miR-26a. Am J Transl Res. 2016;8:2981–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Chen S, Wang M, Yang H, Mao L, He Q, Jin H, Ye ZM, Luo XY, Xia YP, Hu B. LncRNA TUG1 sponges microRNA-9 to promote neurons apoptosis by up-regulated Bcl2l11 under ischemia. Biochem Biophys Res Commun. 2017;485:167–73.

    Article  PubMed  CAS  Google Scholar 

  167. Viereck J, Kumarswamy R, Foinquinos A, Xiao K, Avramopoulos P, Kunz M, Dittrich M, Maetzig T, Zimmer K, Remke J, Just A, Fendrich J, Scherf K, Bolesani E, Schambach A, Weidemann F, Zweigerdt R, de Windt LJ, Engelhardt S, Dandekar T, Batkai S, Thum T. Long noncoding RNA Chast promotes cardiac remodeling. Sci Transl Med. 2016;8:326ra22.

    Article  PubMed  CAS  Google Scholar 

  168. Wang K, Liu F, Zhou LY, Long B, Yuan SM, Wang Y, Liu CY, Sun T, Zhang XJ, Li PF. The long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489. Circ Res. 2014;114:1377–88.

    Article  CAS  PubMed  Google Scholar 

  169. Lai Y, He S, Ma L, Lin H, Ren B, Ma J, Zhu X, Zhuang S. HOTAIR functions as a competing endogenous RNA to regulate PTEN expression by inhibiting miR-19 in cardiac hypertrophy. Mol Cell Biochem. 2017;432:179–87.

    Article  CAS  PubMed  Google Scholar 

  170. Greco S, Zaccagnini G, Perfetti A, Fuschi P, Valaperta R, Voellenkle C, Castelvecchio S, Gaetano C, Finato N, Beltrami AP, Menicanti L, Martelli F. Long noncoding RNA dysregulation in ischemic heart failure. J Transl Med. 2016;14:183.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Vausort M, Wagner DR, Devaux Y. Long noncoding RNAs in patients with acute myocardial infarction. Circ Res. 2014;115:668–77.

    Article  CAS  PubMed  Google Scholar 

  172. Li X, Dai Y, Yan S, Shi Y, Han B, Li J, Cha L, Mu J. Down-regulation of lncRNA KCNQ1OT1 protects against myocardial ischemia/reperfusion injury following acute myocardial infarction. Biochem Biophys Res Commun. 2017;491:1026–33.

    Article  CAS  PubMed  Google Scholar 

  173. Li X, Zhou J, Huang K. Inhibition of the lncRNA Mirt1 attenuates acute myocardial infarction by suppressing NF-kappaB activation. Cell Physiol Biochem. 2017;42:1153–64.

    Article  CAS  PubMed  Google Scholar 

  174. Jiang F, Zhou X, Huang J. Long non-coding RNA-ROR mediates the reprogramming in cardiac hypertrophy. PLoS One. 2016;11:e0152767.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Bravo-San Pedro JM, Kroemer G, Galluzzi L. Autophagy and mitophagy in cardiovascular disease. Circ Res. 2017;120:1812–24.

    Article  CAS  PubMed  Google Scholar 

  176. Geng HH, Li R, Su YM, Xiao J, Pan M, Cai XX, Ji XP. The circular RNA Cdr1as promotes myocardial infarction by mediating the regulation of miR-7a on its target genes expression. PLoS One. 2016;11:e0151753.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Liu J, Li Y, Lin B, Sheng Y, Yang L. HBL1 is a human long noncoding RNA that modulates cardiomyocyte development from pluripotent stem cells by counteracting MIR1. Dev Cell. 2017;42:333–348 e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Lin X, Zhan JK, Wang YJ, Tan P, Chen YY, Deng HQ, Liu YS. Function, role, and clinical application of microRNAs in vascular aging. Biomed Res Int. 2016;2016:6021394.

    PubMed  PubMed Central  Google Scholar 

  179. Liu Y, Zhou D, Li G, Ming X, Tu Y, Tian J, Lu H, Yu B. Long non coding RNA-UCA1 contributes to cardiomyocyte apoptosis by suppression of p27 expression. Cell Physiol Biochem. 2015;35:1986–98.

    Article  CAS  PubMed  Google Scholar 

  180. Zhu XH, Yuan YX, Rao SL, Wang P. LncRNA MIAT enhances cardiac hypertrophy partly through sponging miR-150. Eur Rev Med Pharmacol Sci. 2016;20:3653–60.

    PubMed  Google Scholar 

  181. Zhou X, Zhang W, Jin M, Chen J, Xu W, Kong X. lncRNA MIAT functions as a competing endogenous RNA to upregulate DAPK2 by sponging miR-22-3p in diabetic cardiomyopathy. Cell Death Dis. 2017;8:e2929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Zhang X, Tang X, Liu K, Hamblin MH, Yin KJ. Long noncoding RNA Malat1 regulates cerebrovascular pathologies in ischemic stroke. J Neurosci. 2017;37:1797–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Xin JW, Jiang YG. Long noncoding RNA MALAT1 inhibits apoptosis induced by oxygen-glucose deprivation and reoxygenation in human brain microvascular endothelial cells. Exp Ther Med. 2017;13:1225–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Zhao J, Zhang W, Lin M, Wu W, Jiang P, Tou E, Xue M, Richards A, Jourd'heuil D, Asif A, Zheng D, Singer HA, Miano JM, Long X. MYOSLID is a novel serum response factor-dependent long noncoding RNA that amplifies the vascular smooth muscle differentiation program. Arterioscler Thromb Vasc Biol. 2016;36:2088–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Chen G, Guo H, Song Y, Chang H, Wang S, Zhang M, Liu C. Long noncoding RNA AK055347 is upregulated in patients with atrial fibrillation and regulates mitochondrial energy production in myocardiocytes. Mol Med Rep. 2016;14:5311–7.

    Article  CAS  PubMed  Google Scholar 

  186. Wang W, Wang X, Zhang Y, Li Z, Xie X, Wang J, Gao M, Zhang S, Hou Y. Transcriptome analysis of canine cardiac fat pads: involvement of two novel long non-coding RNAs in atrial fibrillation neural remodeling. J Cell Biochem. 2015;116:809–21.

    Article  CAS  PubMed  Google Scholar 

  187. Li Z, Wang X, Wang W, Du J, Wei J, Zhang Y, Wang J, Hou Y. Altered long non-coding RNA expression profile in rabbit atria with atrial fibrillation: TCONS_00075467 modulates atrial electrical remodeling by sponging miR-328 to regulate CACNA1C. J Mol Cell Cardiol. 2017;108:73–85.

    Article  CAS  PubMed  Google Scholar 

  188. Xu Q, Deng F, Xing Z, Wu Z, Cen B, Xu S, Zhao Z, Nepomuceno R, Bhuiyan MI, Sun D, Wang QJ, Ji A. Long non-coding RNA C2dat1 regulates CaMKIIdelta expression to promote neuronal survival through the NF-kappaB signaling pathway following cerebral ischemia. Cell Death Dis. 2016;7:e2173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Wu Z, Wu P, Zuo X, Yu N, Qin Y, Xu Q, He S, Cen B, Liao W, Ji A. LncRNA-N1LR enhances neuroprotection against ischemic stroke probably by inhibiting p53 phosphorylation. Mol Neurobiol. 2017;54:7670–85.

    Article  CAS  PubMed  Google Scholar 

  190. Qi X, Shao M, Sun H, Shen Y, Meng D, Huo W. Long non-coding RNA SNHG14 promotes microglia activation by regulating miR-145-5p/PLA2G4A in cerebral infarction. Neuroscience. 2017;348:98–106.

    Article  CAS  PubMed  Google Scholar 

  191. Holdt LM, Hoffmann S, Sass K, Langenberger D, Scholz M, Krohn K, Finstermeier K, Stahringer A, Wilfert W, Beutner F, Gielen S, Schuler G, Gabel G, Bergert H, Bechmann I, Stadler PF, Thiery J, Teupser D. Alu elements in ANRIL non-coding RNA at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks. PLoS Genet. 2013;9:e1003588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Yap KL, Li S, Munoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, Gil J, Walsh MJ, Zhou MM. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell. 2010;38:662–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Smith CM, Steitz JA. Classification of gas5 as a multi-small-nucleolar-RNA (snoRNA) host gene and a member of the 5′-terminal oligopyrimidine gene family reveals common features of snoRNA host genes. Mol Cell Biol. 1998;18:6897–909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP. Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal. 2010;3:ra8.

    PubMed  PubMed Central  Google Scholar 

  195. Aprea J, Prenninger S, Dori M, Ghosh T, Monasor LS, Wessendorf E, Zocher S, Massalini S, Alexopoulou D, Lesche M, Dahl A, Groszer M, Hiller M, Calegari F. Transcriptome sequencing during mouse brain development identifies long non-coding RNAs functionally involved in neurogenic commitment. EMBO J. 2013;32:3145–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Sheik Mohamed J, Gaughwin PM, Lim B, Robson P, Lipovich L. Conserved long noncoding RNAs transcriptionally regulated by Oct4 and Nanog modulate pluripotency in mouse embryonic stem cells. RNA. 2010;16:324–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Zhang Y, Zhang M, Xu W, Chen J, Zhou X. The long non-coding RNA H19 promotes cardiomyocyte apoptosis in dilated cardiomyopathy. Oncotarget. 2017;8:28588–94.

    PubMed  PubMed Central  Google Scholar 

  198. Venkatraman A, He XC, Thorvaldsen JL, Sugimura R, Perry JM, Tao F, Zhao M, Christenson MK, Sanchez R, Yu JY, Peng L, Haug JS, Paulson A, Li H, Zhong XB, Clemens TL, Bartolomei MS, Li L. Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence. Nature. 2013;500:345–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Kallen AN, Zhou XB, Xu J, Qiao C, Ma J, Yan L, Lu L, Liu C, Yi JS, Zhang H, Min W, Bennett AM, Gregory RI, Ding Y, Huang Y. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol Cell. 2013;52:101–12.

    Article  CAS  PubMed  Google Scholar 

  200. Monnier P, Martinet C, Pontis J, Stancheva I, Ait-Si-Ali S, Dandolo L. H19 lncRNA controls gene expression of the Imprinted Gene Network by recruiting MBD1. Proc Natl Acad Sci U S A. 2013;110:20693–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Giovarelli M, Bucci G, Ramos A, Bordo D, Wilusz CJ, Chen CY, Puppo M, Briata P, Gherzi R. H19 long noncoding RNA controls the mRNA decay promoting function of KSRP. Proc Natl Acad Sci U S A. 2014;111:E5023–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Yoon JH, Abdelmohsen K, Srikantan S, Yang X, Martindale JL, De S, Huarte M, Zhan M, Becker KG, Gorospe M. LincRNA-p21 suppresses target mRNA translation. Mol Cell. 2012;47:648–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Zhou Y, Zhong Y, Wang Y, Zhang X, Batista DL, Gejman R, Ansell PJ, Zhao J, Weng C, Klibanski A. Activation of p53 by MEG3 non-coding RNA. J Biol Chem. 2007;282:24731–42.

    Article  CAS  PubMed  Google Scholar 

  204. Kaneko S, Bonasio R, Saldana-Meyer R, Yoshida T, Son J, Nishino K, Umezawa A, Reinberg D. Interactions between JARID2 and noncoding RNAs regulate PRC2 recruitment to chromatin. Mol Cell. 2014;53:290–300.

    Article  CAS  PubMed  Google Scholar 

  205. Sanuki R, Onishi A, Koike C, Muramatsu R, Watanabe S, Muranishi Y, Irie S, Uneo S, Koyasu T, Matsui R, Cherasse Y, Urade Y, Watanabe D, Kondo M, Yamashita T, Furukawa T. miR-124a is required for hippocampal axogenesis and retinal cone survival through Lhx2 suppression. Nat Neurosci. 2011;14:1125–34.

    Article  CAS  PubMed  Google Scholar 

  206. Yang L, Lin C, Liu W, Zhang J, Ohgi KA, Grinstein JD, Dorrestein PC, Rosenfeld MG. ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell. 2011;147:773–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Chen R, Kong P, Zhang F, Shu YN, Nie X, Dong LH, Lin YL, Xie XL, Zhao LL, Zhang XJ, Han M. EZH2-mediated alpha-actin methylation needs lncRNA TUG1, and promotes the cortex cytoskeleton formation in VSMCs. Gene. 2017;616:52–7.

    Article  CAS  PubMed  Google Scholar 

  208. Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, Chang HY. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 2007;129:1311–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Portoso M, Ragazzini R, Brencic Z, Moiani A, Michaud A, Vassilev I, Wassef M, Servant N, Sargueil B, Margueron R. PRC2 is dispensable for HOTAIR-mediated transcriptional repression. EMBO J. 2017;36:981–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Terranova R, Yokobayashi S, Stadler MB, Otte AP, van Lohuizen M, Orkin SH, Peters AH. Polycomb group proteins Ezh2 and Rnf2 direct genomic contraction and imprinted repression in early mouse embryos. Dev Cell. 2008;15:668–79.

    Article  CAS  PubMed  Google Scholar 

  211. Zhang H, Zeitz MJ, Wang H, Niu B, Ge S, Li W, Cui J, Wang G, Qian G, Higgins MJ, Fan X, Hoffman AR, Hu JF. Long noncoding RNA-mediated intrachromosomal interactions promote imprinting at the Kcnq1 locus. J Cell Biol. 2014;204:61–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Wang Y, Xu Z, Jiang J, Xu C, Kang J, Xiao L, Wu M, Xiong J, Guo X, Liu H. Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev Cell. 2013;25:69–80.

    Article  CAS  PubMed  Google Scholar 

  213. Piwecka M, Glazar P, Hernandez-Miranda LR, Memczak S, Wolf SA, Rybak-Wolf A, Filipchyk A, Klironomos F, Cerda Jara CA, Fenske P, Trimbuch T, Zywitza V, Plass M, Schreyer L, Ayoub S, Kocks C, Kuhn R, Rosenmund C, Birchmeier C, Rajewsky N. Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science. 2017;357

    Google Scholar 

  214. Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, Loewer A, Ziebold U, Landthaler M, Kocks C, le Noble F, Rajewsky N. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495:333–8.

    Article  CAS  PubMed  Google Scholar 

  215. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8.

    Article  CAS  PubMed  Google Scholar 

  216. Arun G, Diermeier S, Akerman M, Chang KC, Wilkinson JE, Hearn S, Kim Y, MacLeod AR, Krainer AR, Norton L, Brogi E, Egeblad M, Spector DL. Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes Dev. 2016;30:34–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett CF, Sharma A, Bubulya PA, Blencowe BJ, Prasanth SG, Prasanth KV. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell. 2010;39:925–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Bernard D, Prasanth KV, Tripathi V, Colasse S, Nakamura T, Xuan Z, Zhang MQ, Sedel F, Jourdren L, Coulpier F, Triller A, Spector DL, Bessis A. A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO J. 2010;29:3082–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Ip JY, Sone M, Nashiki C, Pan Q, Kitaichi K, Yanaka K, Abe T, Takao K, Miyakawa T, Blencowe BJ, Nakagawa S. Gomafu lncRNA knockout mice exhibit mild hyperactivity with enhanced responsiveness to the psychostimulant methamphetamine. Sci Rep. 2016;6:27204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Cai X, Cullen BR. The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA. 2007;13:313–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43:904–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154:26–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011;469:343–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Cajigas I, Leib DE, Cochrane J, Luo H, Swyter KR, Chen S, Clark BS, Thompson J, Yates JR 3rd, Kingston RE, Kohtz JD. Evf2 lncRNA/BRG1/DLX1 interactions reveal RNA-dependent inhibition of chromatin remodeling. Development. 2015;142:2641–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Kaneko S, Son J, Bonasio R, Shen SS, Reinberg D. Nascent RNA interaction keeps PRC2 activity poised and in check. Genes Dev. 2014;28:1983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Di Ruscio A, Ebralidze AK, Benoukraf T, Amabile G, Goff LA, Terragni J, Figueroa ME, De Figueiredo Pontes LL, Alberich-Jorda M, Zhang P, Wu M, D'Alo F, Melnick A, Leone G, Ebralidze KK, Pradhan S, Rinn JL, Tenen DG. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature. 2013;503:371–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  227. Portoso M, Ragazzinni R, Brenčič Ž, Moiani A, Michaud A, Vassilev I, Wassef M, Servant N, Sargueil B, Margueron R. PRC2 is dispensable for HOTAIR-mediated transcriptional repression. EMBO J. 2017;36:981–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Engreitz JM, Sirokman K, McDonel P, Shishkin AA, Surka C, Russell P, Grossman SR, Chow AY, Guttman M, Lander ES. RNA-RNA interactions enable specific targeting of noncoding RNAs to nascent Pre-mRNAs and chromatin sites. Cell. 2014;159:188–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. McHugh CA, Chen CK, Chow A, Surka CF, Tran C, McDonel P, Pandya-Jones A, Blanco M, Burghard C, Moradian A, Sweredoski MJ, Shishkin AA, Su J, Lander ES, Hess S, Plath K, Guttman M. The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3. Nature. 2015;521:232–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Chu C, Zhang QC, da Rocha ST, Flynn RA, Bharadwaj M, Calabrese JM, Magnuson T, Heard E, Chang HY. Systematic discovery of Xist RNA binding proteins. Cell. 2015;161:404–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. West JA, Davis CP, Sunwoo H, Simon MD, Sadreyev RI, Wang PI, Tolstorukov MY, Kingston RE. The long noncoding RNAs NEAT1 and MALAT1 bind active chromatin sites. Mol Cell. 2014;55:791–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Ramirez F, Lingg T, Toscano S, Lam KC, Georgiev P, Chung HR, Lajoie BR, de Wit E, Zhan Y, de Laat W, Dekker J, Manke T, Akhtar A. High-affinity sites form an interaction network to facilitate spreading of the MSL complex across the X chromosome in drosophila. Mol Cell. 2015;60:146–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Engreitz JM, Ollikainen N, Guttman M. Long non-coding RNAs: spatial amplifiers that control nuclear structure and gene expression. Nat Rev Mol Cell Biol. 2016;17:756–70.

    Article  CAS  PubMed  Google Scholar 

  234. Sunwoo H, Wu JY, Lee JT. The Xist RNA-PRC2 complex at 20-nm resolution reveals a low Xist stoichiometry and suggests a hit-and-run mechanism in mouse cells. Proc Natl Acad Sci U S A. 2015;112:E4216–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Simon MD, Pinter SF, Fang R, Sarma K, Rutenberg-Schoenberg M, Bowman SK, Kesner BA, Maier VK, Kingston RE, Lee JT. High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation. Nature. 2013;504:465–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Jeon Y, Lee JT. YY1 tethers Xist RNA to the inactive X nucleation center. Cell. 2011;146:119–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Engreitz JM, Pandya-Jones A, McDonel P, Shishkin A, Sirokman K, Surka C, Kadri S, Xing J, Goren A, Lander ES, Plath K, Guttman M. The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science. 2013;341:1237973.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  238. Minajigi A, Froberg J, Wei C, Sunwoo H, Kesner B, Colognori D, Lessing D, Payer B, Boukhali M, Haas W, Lee JT. Chromosomes. A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation. Science. 2015;349

    Google Scholar 

  239. Ilik IA, Quinn JJ, Georgiev P, Tavares-Cadete F, Maticzka D, Toscano S, Wan Y, Spitale RC, Luscombe N, Backofen R, Chang HY, Akhtar A. Tandem stem-loops in roX RNAs act together to mediate X chromosome dosage compensation in Drosophila. Mol Cell. 2013;51:156–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Somarowthu S, Legiewicz M, Chillon I, Marcia M, Liu F, Pyle AM. HOTAIR forms an intricate and modular secondary structure. Mol Cell. 2015;58:353–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Spitale RC, Flynn RA, Zhang QC, Crisalli P, Lee B, Jung JW, Kuchelmeister HY, Batista PJ, Torre EA, Kool ET, Chang HY. Structural imprints in vivo decode RNA regulatory mechanisms. Nature. 2015;519:486–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Martin WJ, Reiter NJ. Structural roles of noncoding RNAs in the heart of enzymatic complexes. Biochemistry. 2017;56:3–13.

    Article  CAS  PubMed  Google Scholar 

  243. Blythe AJ, Fox AH, Bond CS. The ins and outs of lncRNA structure: How, why and what comes next? Biochim Biophys Acta. 2016;1859:46–58.

    Article  CAS  PubMed  Google Scholar 

  244. da Rocha ST, Boeva V, Escamilla-Del-Arenal M, Ancelin K, Granier C, Matias NR, Sanulli S, Chow J, Schulz E, Picard C, Kaneko S, Helin K, Reinberg D, Stewart AF, Wutz A, Margueron R, Heard E. Jarid2 is implicated in the initial xist-induced targeting of PRC2 to the inactive X chromosome. Mol Cell. 2014;53:301–16.

    Article  PubMed  CAS  Google Scholar 

  245. Almeida M, Pintacuda G, Masui O, Koseki Y, Gdula M, Cerase A, Brown D, Mould A, Innocent C, Nakayama M, Schermelleh L, Nesterova TB, Koseki H, Brockdorff N. PCGF3/5-PRC1 initiates Polycomb recruitment in X chromosome inactivation. Science. 2017;356:1081–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Wutz A, Rasmussen TP, Jaenisch R. Chromosomal silencing and localization are mediated by different domains of Xist RNA. Nat Genet. 2002;30:167–74.

    Article  CAS  PubMed  Google Scholar 

  247. Chen CK, Blanco M, Jackson C, Aznauryan E, Ollikainen N, Surka C, Chow A, Cerase A, McDonel P, Guttman M. Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing. Science. 2016;354:468–72.

    Article  CAS  PubMed  Google Scholar 

  248. Hnisz D, Day DS, Young RA. Insulated neighborhoods: structural and functional units of mammalian gene control. Cell. 2016;167:1188–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Bonev B, Cavalli G. Organization and function of the 3D genome. Nat Rev Genet. 2016;17:661–78.

    Article  CAS  PubMed  Google Scholar 

  250. Kaikkonen MU, Spann NJ, Heinz S, Romanoski CE, Allison KA, Stender JD, Chun HB, Tough DF, Prinjha RK, Benner C, Glass CK. Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell. 2013;51:310–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Schaukowitch K, Joo JY, Liu X, Watts JK, Martinez C, Kim TK. Enhancer RNA facilitates NELF release from immediate early genes. Mol Cell. 2014;56:29–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Pefanis E, Wang J, Rothschild G, Lim J, Kazadi D, Sun J, Federation A, Chao J, Elliott O, Liu ZP, Economides AN, Bradner JE, Rabadan R, Basu U. RNA exosome-regulated long non-coding RNA transcription controls super-enhancer activity. Cell. 2015;161:774–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Ounzain S, Pedrazzini T. Super-enhancer lncs to cardiovascular development and disease. Biochim Biophys Acta. 2016;1863:1953–60.

    Article  CAS  PubMed  Google Scholar 

  254. Mousavi K, Zare H, Dell'orso S, Grontved L, Gutierrez-Cruz G, Derfoul A, Hager GL, Sartorelli V. eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci. Mol Cell. 2013;51:606–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Lam MT, Cho H, Lesch HP, Gosselin D, Heinz S, Tanaka-Oishi Y, Benner C, Kaikkonen MU, Kim AS, Kosaka M, Lee CY, Watt A, Grossman TR, Rosenfeld MG, Evans RM, Glass CK. Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. Nature. 2013;498:511–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Lai F, Orom UA, Cesaroni M, Beringer M, Taatjes DJ, Blobel GA, Shiekhattar R. Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature. 2013;494:497–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Natoli G, Andrau JC. Noncoding transcription at enhancers: general principles and functional models. Annu Rev Genet. 2012;46:1–19.

    Article  CAS  PubMed  Google Scholar 

  258. Gribnau J, Diderich K, Pruzina S, Calzolari R, Fraser P. Intergenic transcription and developmental remodeling of chromatin subdomains in the human beta-globin locus. Mol Cell. 2000;5:377–86.

    Article  CAS  PubMed  Google Scholar 

  259. Venkatesh S, Workman JL. Histone exchange, chromatin structure and the regulation of transcription. Nat Rev Mol Cell Biol. 2015;16:178–89.

    Article  CAS  PubMed  Google Scholar 

  260. Dekker J, Mirny L. The 3D genome as moderator of chromosomal communication. Cell. 2016;164:1110–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Werner MS, Ruthenburg AJ. Nuclear fractionation reveals thousands of chromatin-tethered noncoding RNAs adjacent to active genes. Cell Rep. 2015;12:1089–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Werner MS, Sullivan MA, Shah RN, Nadadur RD, Grzybowski AT, Galat V, Moskowitz IP, Ruthenburg AJ. Chromatin-enriched lncRNAs can act as cell-type specific activators of proximal gene transcription. Nat Struct Mol Biol. 2017;24:596–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Pandey RR, Mondal T, Mohammad F, Enroth S, Redrup L, Komorowski J, Nagano T, Mancini-Dinardo D, Kanduri C. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol Cell. 2008;32:232–46.

    Article  CAS  PubMed  Google Scholar 

  264. Mohammad F, Pandey RR, Nagano T, Chakalova L, Mondal T, Fraser P, Kanduri C. Kcnq1ot1/Lit1 noncoding RNA mediates transcriptional silencing by targeting to the perinucleolar region. Mol Cell Biol. 2008;28:3713–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Shechner DM, Hacisuleyman E, Younger ST, Rinn JL. Multiplexable, locus-specific targeting of long RNAs with CRISPR-Display. Nat Methods. 2015;12:664–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Zhang Y, Zhang XO, Chen T, Xiang JF, Yin QF, Xing YH, Zhu S, Yang L, Chen LL. Circular intronic long noncoding RNAs. Mol Cell. 2013;51:792–806.

    Article  CAS  PubMed  Google Scholar 

  267. Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, Zhong G, Yu B, Hu W, Dai L, Zhu P, Chang Z, Wu Q, Zhao Y, Jia Y, Xu P, Liu H, Shan G. Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2015;22:256–64.

    Article  PubMed  CAS  Google Scholar 

  268. Chedin F. Nascent connections: R-loops and chromatin patterning. Trends Genet. 2016;32:828–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Sanz LA, Hartono SR, Lim YW, Steyaert S, Rajpurkar A, Ginno PA, Xu X, Chedin F. Prevalent. Dynamic, and Conserved R-Loop Structures Associate with Specific Epigenomic Signatures in Mammals, Mol Cell. 2016;63:167–78.

    CAS  PubMed  Google Scholar 

  270. Cloutier SC, Wang S, Ma WK, Al Husini N, Dhoondia Z, Ansari A, Pascuzzi PE, Tran EJ. Regulated formation of lncRNA-DNA hybrids enables faster transcriptional induction and environmental adaptation. Mol Cell. 2016;62:148.

    Article  CAS  PubMed  Google Scholar 

  271. Ng SY, Bogu GK, Soh BS, Stanton LW. The long noncoding RNA RMST interacts with SOX2 to regulate neurogenesis. Mol Cell. 2013;51:349–59.

    Article  CAS  PubMed  Google Scholar 

  272. Tang R, Zhang G, Wang YC, Mei X, Chen SY. The long non-coding RNA GAS5 regulates transforming growth factor beta (TGF-beta)-induced smooth muscle cell differentiation via RNA Smad-binding elements. J Biol Chem. 2017;292:14270–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Xue Z, Hennelly S, Doyle B, Gulati AA, Novikova IV, Sanbonmatsu KY, Boyer LA. A G-rich motif in the lncRNA braveheart interacts with a zinc-finger transcription factor to specify the cardiovascular lineage. Mol Cell. 2016;64:37–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Ozsolak F, Kapranov P, Foissac S, Kim SW, Fishilevich E, Monaghan AP, John B, Milos PM. Comprehensive polyadenylation site maps in yeast and human reveal pervasive alternative polyadenylation. Cell. 2010;143:1018–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Chu C, Qu K, Zhong FL, Artandi SE, Chang HY. Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. Mol Cell. 2011;44:667–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Zhao J, Ohsumi TK, Kung JT, Ogawa Y, Grau DJ, Sarma K, Song JJ, Kingston RE, Borowsky M, Lee JT. Genome-wide identification of polycomb-associated RNAs by RIP-seq. Mol Cell. 2010;40:939–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Hongay CF, Grisafi PL, Galitski T, Fink GR. Antisense transcription controls cell fate in Saccharomyces cerevisiae. Cell. 2006;127:735–45.

    Article  CAS  PubMed  Google Scholar 

  278. Beltran M, Puig I, Pena C, Garcia JM, Alvarez AB, Pena R, Bonilla F, de Herreros AG. A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. Genes Dev. 2008;22:756–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Munroe SH, Lazar MA. Inhibition of c-erbA mRNA splicing by a naturally occurring antisense RNA. J Biol Chem. 1991;266:22083–6.

    CAS  PubMed  Google Scholar 

  280. Krystal GW, Armstrong BC, Battey JF. N-myc mRNA forms an RNA-RNA duplex with endogenous antisense transcripts. Mol Cell Biol. 1990;10:4180–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell. 2011;146:353–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Tay Y, Kats L, Salmena L, Weiss D, Tan SM, Ala U, Karreth F, Poliseno L, Provero P, Di Cunto F, Lieberman J, Rigoutsos I, Pandolfi PP. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell. 2011;147:344–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, Tramontano A, Bozzoni I. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell. 2011;147:358–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Thomson DW, Dinger ME. Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet. 2016;17:272–83.

    Article  CAS  PubMed  Google Scholar 

  285. Denzler R, Agarwal V, Stefano J, Bartel DP, Stoffel M. Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. Mol Cell. 2014;54:766–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Bosson AD, Zamudio JR, Sharp PA. Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition. Mol Cell. 2014;56:347–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  287. Karreth FA, Reschke M, Ruocco A, Ng C, Chapuy B, Leopold V, Sjoberg M, Keane TM, Verma A, Ala U, Tay Y, Wu D, Seitzer N, Velasco-Herrera Mdel C, Bothmer A, Fung J, Langellotto F, Rodig SJ, Elemento O, Shipp MA, Adams DJ, Chiarle R, Pandolfi PP. The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo. Cell. 2015;161:319–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Denzler R, McGeary SE, Title AC, Agarwal V, Bartel DP, Stoffel M. Impact of MicroRNA Levels. Target-Site Complementarity, and Cooperativity on Competing Endogenous RNA-Regulated Gene Expression, Mol Cell. 2016;64:565–79.

    CAS  PubMed  Google Scholar 

  289. Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3' UTRs via Alu elements. Nature. 2011;470:284–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Damas ND, Marcatti M, Come C, Christensen LL, Nielsen MM, Baumgartner R, Gylling HM, Maglieri G, Rundsten CF, Seemann SE, Rapin N, Thezenas S, Vang S, Orntoft T, Andersen CL, Pedersen JS, Lund AH. SNHG5 promotes colorectal cancer cell survival by counteracting STAU1-mediated mRNA destabilization. Nat Commun. 2016;7:13875.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. Lu Z, Zhang QC, Lee B, Flynn RA, Smith MA, Robinson JT, Davidovich C, Gooding AR, Goodrich KJ, Mattick JS, Mesirov JP, Cech TR, Chang HY. RNA duplex map in living cells reveals higher-order transcriptome structure. Cell. 2016;165:1267–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Aw JG, Shen Y, Wilm A, Sun M, Lim XN, Boon KL, Tapsin S, Chan YS, Tan CP, Sim AY, Zhang T, Susanto TT, Fu Z, Nagarajan N, Wan Y. In vivo mapping of eukaryotic RNA interactomes reveals principles of higher-order organization and regulation. Mol Cell. 2016;62:603–17.

    Article  CAS  PubMed  Google Scholar 

  293. Fei J, Cui XB, Wang JN, Dong K, Chen SY. ADAR1-mediated RNA editing. A Novel Mechanism Controlling Phenotypic Modulation of Vascular Smooth Muscle Cells, Circ Res. 2016;119:463–9.

    CAS  PubMed  Google Scholar 

  294. Stellos K, Gatsiou A, Stamatelopoulos K, Perisic Matic L, John D, Lunella FF, Jae N, Rossbach O, Amrhein C, Sigala F, Boon RA, Furtig B, Manavski Y, You X, Uchida S, Keller T, Boeckel JN, Franco-Cereceda A, Maegdefessel L, Chen W, Schwalbe H, Bindereif A, Eriksson P, Hedin U, Zeiher AM, Dimmeler S. Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation. Nat Med. 2016;22:1140–50.

    Article  CAS  PubMed  Google Scholar 

  295. Zheng S, Vuong BQ, Vaidyanathan B, Lin JY, Huang FT, Chaudhuri J. Non-coding RNA generated following lariat debranching mediates targeting of AID to DNA. Cell. 2015;161:762–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Carrieri C, Cimatti L, Biagioli M, Beugnet A, Zucchelli S, Fedele S, Pesce E, Ferrer I, Collavin L, Santoro C, Forrest AR, Carninci P, Biffo S, Stupka E, Gustincich S. Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature. 2012;491:454–7.

    Article  CAS  PubMed  Google Scholar 

  297. Abdelmohsen K, Panda AC, Munk R, Grammatikakis I, Dudekula DB, De S, Kim J, Noh JH, Kim KM, Martindale JL, Gorospe M. Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1. RNA Biol. 2017:1–9.

    Google Scholar 

  298. Lebedeva S, Jens M, Theil K, Schwanhausser B, Selbach M, Landthaler M, Rajewsky N. Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR. Mol Cell. 2011;43:340–52.

    Article  CAS  PubMed  Google Scholar 

  299. Frith MC, Bailey TL, Kasukawa T, Mignone F, Kummerfeld SK, Madera M, Sunkara S, Furuno M, Bult CJ, Quackenbush J, Kai C, Kawai J, Carninci P, Hayashizaki Y, Pesole G, Mattick JS. Discrimination of non-protein-coding transcripts from protein-coding mRNA. RNA Biol. 2006;3:40–8.

    Article  CAS  PubMed  Google Scholar 

  300. You X, Vlatkovic I, Babic A, Will T, Epstein I, Tushev G, Akbalik G, Wang M, Glock C, Quedenau C, Wang X, Hou J, Liu H, Sun W, Sambandan S, Chen T, Schuman EM, Chen W. Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat Neurosci. 2015;18:603–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Pamudurti NR, Bartok O, Jens M, Ashwal-Fluss R, Stottmeister C, Ruhe L, Hanan M, Wyler E, Perez-Hernandez D, Ramberger E, Shenzis S, Samson M, Dittmar G, Landthaler M, Chekulaeva M, Rajewsky N, Kadener S. Translation of CircRNAs. Mol Cell. 2017;66(1):9–21.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. Legnini I, Di Timoteo G, Rossi F, Morlando M, Briganti F, Sthandier O, Fatica A, Santini T, Andronache A, Wade M, Laneve P, Rajewsky N, Bozzoni I. Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Mol Cell. 2017;66(1):22–37.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  303. Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell. 2009;136:731–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  304. Bassett AR, Akhtar A, Barlow DP, Bird AP, Brockdorff N, Duboule D, Ephrussi A, Ferguson-Smith AC, Gingeras TR, Haerty W, Higgs DR, Miska EA, Ponting CP. Considerations when investigating lncRNA function in vivo. elife. 2014;3:e03058.

    Article  PubMed  PubMed Central  Google Scholar 

  305. Fabre PJ, Leleu M, Mormann BH, Lopez-Delisle L, Noordermeer D, Beccari L, Duboule D. Large scale genomic reorganization of topological domains at the HoxD locus. Genome Biol. 2017;18:149.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  306. Srivastava D. Making or breaking the heart: from lineage determination to morphogenesis. Cell. 2006;126:1037–48.

    Article  CAS  PubMed  Google Scholar 

  307. Bruneau BG. Signaling and transcriptional networks in heart development and regeneration. Cold Spring Harb Perspect Biol. 2013;5:a008292.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  308. Wamstad JA, Alexander JM, Truty RM, Shrikumar A, Li F, Eilertson KE, Ding H, Wylie JN, Pico AR, Capra JA, Erwin G, Kattman SJ, Keller GM, Srivastava D, Levine SS, Pollard KS, Holloway AK, Boyer LA, Bruneau BG. Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage. Cell. 2012;151:206–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  309. Zhu JG, Shen YH, Liu HL, Liu M, Shen YQ, Kong XQ, Song GX, Qian LM. Long noncoding RNAs expression profile of the developing mouse heart. J Cell Biochem. 2014;115:910–8.

    Article  CAS  PubMed  Google Scholar 

  310. Matkovich SJ, Edwards JR, Grossenheider TC, de Guzman Strong C, Dorn GW 2nd. Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs. Proc Natl Acad Sci U S A. 2014;111:12264–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  311. Sauvageau M, Goff LA, Lodato S, Bonev B, Groff AF, Gerhardinger C, Sanchez-Gomez DB, Hacisuleyman E, Li E, Spence M, Liapis SC, Mallard W, Morse M, Swerdel MR, D'Ecclessis MF, Moore JC, Lai V, Gong G, Yancopoulos GD, Frendewey D, Kellis M, Hart RP, Valenzuela DM, Arlotta P, Rinn JL. Multiple knockout mouse models reveal lincRNAs are required for life and brain development. elife. 2013;2:e01749.

    Article  PubMed  PubMed Central  Google Scholar 

  312. Delas MJ, Hannon GJ. lncRNAs in development and disease: from functions to mechanisms. Open Biol. 2017;7

    Google Scholar 

  313. Chen R, Liu Y, Zhuang H, Yang B, Hei K, Xiao M, Hou C, Gao H, Zhang X, Jia C, Li L, Li Y, Zhang N. Quantitative proteomics reveals that long non-coding RNA MALAT1 interacts with DBC1 to regulate p53 acetylation. Nucleic Acids Res. 2017;45:9947–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  314. Ishii N, Ozaki K, Sato H, Mizuno H, Saito S, Takahashi A, Miyamoto Y, Ikegawa S, Kamatani N, Hori M, Saito S, Nakamura Y, Tanaka T. Identification of a novel non-coding RNA. MIAT, that confers risk of myocardial infarction, J Hum Genet. 2006;51:1087–99.

    CAS  PubMed  Google Scholar 

  315. Diabetes Genetics Initiative of Broad Institute of, H., Mit, L. U., Novartis Institutes of BioMedical, R., Saxena, R., Voight, B. F., Lyssenko, V., Burtt, N. P., de Bakker, P. I., Chen, H., Roix, J. J., Kathiresan, S., Hirschhorn, J. N., Daly, M. J., Hughes, T. E., Groop, L., Altshuler, D., Almgren, P., Florez, J. C., Meyer, J., Ardlie, K., Bengtsson Bostrom, K., Isomaa, B., Lettre, G., Lindblad, U., Lyon, H. N., Melander, O., Newton-Cheh, C., Nilsson, P., Orho-Melander, M., Rastam, L., Speliotes, E. K., Taskinen, M. R., Tuomi, T., Guiducci, C., Berglund, A., Carlson, J., Gianniny, L., Hackett, R., Hall, L., Holmkvist, J., Laurila, E., Sjogren, M., Sterner, M., Surti, A., Svensson, M., Svensson, M., Tewhey, R., Blumenstiel, B., Parkin, M., Defelice, M., Barry, R., Brodeur, W., Camarata, J., Chia, N., Fava, M., Gibbons, J., Handsaker, B., Healy, C., Nguyen, K., Gates, C., Sougnez, C., Gage, D., Nizzari, M., Gabriel, S. B., Chirn, G. W., Ma, Q., Parikh, H., Richardson, D., Ricke, D. & Purcell, S. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316:1331–6.

    Article  CAS  Google Scholar 

  316. Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU, Prokunina-Olsson L, Ding CJ, Swift AJ, Narisu N, Hu T, Pruim R, Xiao R, Li XY, Conneely KN, Riebow NL, Sprau AG, Tong M, White PP, Hetrick KN, Barnhart MW, Bark CW, Goldstein JL, Watkins L, Xiang F, Saramies J, Buchanan TA, Watanabe RM, Valle TT, Kinnunen L, Abecasis GR, Pugh EW, Doheny KF, Bergman RN, Tuomilehto J, Collins FS, Boehnke M. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007;316:1341–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  317. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JR, Rayner NW, Freathy RM, Barrett JC, Shields B, Morris AP, Ellard S, Groves CJ, Harries LW, Marchini JL, Owen KR, Knight B, Cardon LR, Walker M, Hitman GA, Morris AD, Doney AS, Wellcome Trust Case Control C, McCarthy MI, Hattersley AT. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007;316:1336–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  318. Dandona S, Stewart AF, Chen L, Williams K, So D, O'Brien E, Glover C, Lemay M, Assogba O, Vo L, Wang YQ, Labinaz M, Wells GA, McPherson R, Roberts R. Gene dosage of the common variant 9p21 predicts severity of coronary artery disease. J Am Coll Cardiol. 2010;56:479–86.

    Article  CAS  PubMed  Google Scholar 

  319. Yu W, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP, Cui H. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature. 2008;451:202–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  320. Kotake Y, Nakagawa T, Kitagawa K, Suzuki S, Liu N, Kitagawa M, Xiong Y. Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene. 2011;30:1956–62.

    Article  CAS  PubMed  Google Scholar 

  321. Kuo CL, Murphy AJ, Sayers S, Li R, Yvan-Charvet L, Davis JZ, Krishnamurthy J, Liu Y, Puig O, Sharpless NE, Tall AR, Welch CL. Cdkn2a is an atherosclerosis modifier locus that regulates monocyte/macrophage proliferation. Arterioscler Thromb Vasc Biol. 2011;31:2483–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  322. Zhou X, Han X, Wittfeldt A, Sun J, Liu C, Wang X, Gan LM, Cao H, Liang Z. Long non-coding RNA ANRIL regulates inflammatory responses as a novel component of NF-kappaB pathway. RNA Biol. 2016;13:98–108.

    Article  PubMed  Google Scholar 

  323. Visel A, Zhu Y, May D, Afzal V, Gong E, Attanasio C, Blow MJ, Cohen JC, Rubin EM, Pennacchio LA. Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature. 2010;464:409–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  324. Meijer-Spierings AH. Is there a relationship between social status and interpersonal behavior? Tijdschr Voor Ziekenverpl. 1966;19:208–12.

    CAS  Google Scholar 

  325. Chen L, Yang W, Guo Y, Chen W, Zheng P, Zeng J, Tong W. Exosomal lncRNA GAS5 regulates the apoptosis of macrophages and vascular endothelial cells in atherosclerosis. PLoS One. 2017;12:e0185406.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  326. Li MJ, Wang P, Liu X, Lim EL, Wang Z, Yeager M, Wong MP, Sham PC, Chanock SJ, Wang J. GWASdb: a database for human genetic variants identified by genome-wide association studies. Nucleic Acids Res. 2012;40:D1047–54.

    Article  CAS  PubMed  Google Scholar 

  327. Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M, Widdowson PS, Williams GM, Reynet C. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 2006;3:167–75.

    Article  CAS  PubMed  Google Scholar 

  328. Guevara NV, Kim HS, Antonova EI, Chan L. The absence of p53 accelerates atherosclerosis by increasing cell proliferation in vivo. Nat Med. 1999;5:335–9.

    Article  CAS  PubMed  Google Scholar 

  329. Schober A, Nazari-Jahantigh M, Wei Y, Bidzhekov K, Gremse F, Grommes J, Megens RT, Heyll K, Noels H, Hristov M, Wang S, Kiessling F, Olson EN, Weber C. MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat Med. 2014;20:368–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  330. Feng J, Liang J, Li J, Li Y, Liang H, Zhao X, McNutt MA, Yin Y. PTEN controls the DNA replication process through MCM2 in response to replicative stress. Cell Rep. 2015;13:1295–303.

    Article  CAS  PubMed  Google Scholar 

  331. Ounzain S, Micheletti R, Beckmann T, Schroen B, Alexanian M, Pezzuto I, Crippa S, Nemir M, Sarre A, Johnson R, Dauvillier J, Burdet F, Ibberson M, Guigo R, Xenarios I, Heymans S, Pedrazzini T. Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. Eur Heart J. 2015;36:353–68a.

    Article  CAS  PubMed  Google Scholar 

  332. Suzuki HI, Young RA, Sharp PA. Super-enhancer-mediated RNA processing revealed by integrative MicroRNA network analysis. Cell. 2017;168:1000–1014 e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  333. Foroud T, Koller DL, Lai D, Sauerbeck L, Anderson C, Ko N, Deka R, Mosley TH, Fornage M, Woo D, Moomaw CJ, Hornung R, Huston J, Meissner I, Bailey-Wilson JE, Langefeld C, Rouleau G, Connolly ES, Worrall BB, Kleindorfer D, Flaherty ML, Martini S, Mackey J, De Los Rios La Rosa F, Brown RD Jr, Broderick JP, FIA Study Investigators. Genome-wide association study of intracranial aneurysms confirms role of Anril and SOX17 in disease risk. Stroke. 2012;43:2846–52.

    Article  CAS  Google Scholar 

  334. Hashikata H, Liu W, Inoue K, Mineharu Y, Yamada S, Nanayakkara S, Matsuura N, Hitomi T, Takagi Y, Hashimoto N, Miyamoto S, Koizumi A. Confirmation of an association of single-nucleotide polymorphism rs1333040 on 9p21 with familial and sporadic intracranial aneurysms in Japanese patients. Stroke. 2010;41:1138–44.

    Article  CAS  PubMed  Google Scholar 

  335. Lin L, Gu ZT, Chen WH, Cao KJ. Increased expression of the long non-coding RNA ANRIL promotes lung cancer cell metastasis and correlates with poor prognosis. Diagn Pathol. 2015;10:14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  336. Qiu JJ, Lin YY, Ding JX, Feng WW, Jin HY, Hua KQ. Long non-coding RNA ANRIL predicts poor prognosis and promotes invasion/metastasis in serous ovarian cancer. Int J Oncol. 2015;46:2497–505.

    Article  CAS  PubMed  Google Scholar 

  337. Sun Z, Ou C, Ren W, Xie X, Li X, Li G. Downregulation of long non-coding RNA ANRIL suppresses lymphangiogenesis and lymphatic metastasis in colorectal cancer. Oncotarget. 2016;7:47536–55.

    PubMed  PubMed Central  Google Scholar 

  338. Zhao JJ, Hao S, Wang LL, Hu CY, Zhang S, Guo LJ, Zhang G, Gao B, Jiang Y, Tian WG, Luo DL. Long non-coding RNA ANRIL promotes the invasion and metastasis of thyroid cancer cells through TGF-beta/Smad signaling pathway. Oncotarget. 2016;7:57903–18.

    PubMed  PubMed Central  Google Scholar 

  339. Haas J, Mester S, Lai A, Frese KS, Sedaghat-Hamedani F, Kayvanpour E, Rausch T, Nietsch R, Boeckel JN, Carstensen A, Volkers M, Dietrich C, Pils D, Amr A, Holzer DB, Martins Bordalo D, Oehler D, Weis T, Mereles D, Buss S, Riechert E, Wirsz E, Wuerstle M, Korbel JO, Keller A, Katus HA, Posch AE, Meder B. Genomic structural variations lead to dysregulation of important coding and non-coding RNA species in dilated cardiomyopathy. EMBO Mol: Med; 2017.

    Google Scholar 

  340. Yang W, Li Y, He F, Wu H. Microarray profiling of long non-coding RNA (lncRNA) associated with hypertrophic cardiomyopathy. BMC Cardiovasc Disord. 2015;15:62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  341. Song G, Shen Y, Zhu J, Liu H, Liu M, Shen YQ, Zhu S, Kong X, Yu Z, Qian L. Integrated analysis of dysregulated lncRNA expression in fetal cardiac tissues with ventricular septal defect. PLoS One. 2013;8:e77492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  342. Gu M, Zheng A, Tu W, Zhao J, Li L, Li M, Han S, Hu X, Zhu J, Pan Y, Xu J, Yu Z. Circulating LncRNAs as Novel. Non-Invasive Biomarkers for Prenatal Detection of Fetal Congenital Heart Defects, Cell Physiol Biochem. 2016;38:1459–71.

    CAS  PubMed  Google Scholar 

  343. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  344. Liao X, Sluimer JC, Wang Y, Subramanian M, Brown K, Pattison JS, Robbins J, Martinez J, Tabas I. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 2012;15:545–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  345. Liesa M, Shirihai OS. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 2013;17:491–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  346. Brown DA, Perry JB, Allen ME, Sabbah HN, Stauffer BL, Shaikh SR, Cleland JG, Colucci WS, Butler J, Voors AA, Anker SD, Pitt B, Pieske B, Filippatos G, Greene SJ, Gheorghiade M. Expert consensus document: mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol. 2017;14:238–50.

    Article  CAS  PubMed  Google Scholar 

  347. Zhao Y, Samal E, Srivastava D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature. 2005;436:214–20.

    Article  CAS  PubMed  Google Scholar 

  348. Lu CX, Gong HR, Liu XY, Wang J, Zhao CM, Huang RT, Xue S, Yang YQ. A novel HAND2 loss-of-function mutation responsible for tetralogy of Fallot. Int J Mol Med. 2016;37:445–51.

    Article  CAS  PubMed  Google Scholar 

  349. Zhang M, Gu H, Xu W, Zhou X. Down-regulation of lncRNA MALAT1 reduces cardiomyocyte apoptosis and improves left ventricular function in diabetic rats. Int J Cardiol. 2016;203:214–6.

    Article  PubMed  Google Scholar 

  350. Newton-Cheh C, Eijgelsheim M, Rice KM, de Bakker PI, Yin X, Estrada K, Bis JC, Marciante K, Rivadeneira F, Noseworthy PA, Sotoodehnia N, Smith NL, Rotter JI, Kors JA, Witteman JC, Hofman A, Heckbert SR, O'Donnell CJ, Uitterlinden AG, Psaty BM, Lumley T, Larson MG, Stricker BH. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat Genet. 2009;41:399–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  351. Lu Y, Zhang Y, Wang N, Pan Z, Gao X, Zhang F, Zhang Y, Shan H, Luo X, Bai Y, Sun L, Song W, Xu C, Wang Z, Yang B. MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation. 2010;122:2378–87.

    Article  CAS  PubMed  Google Scholar 

  352. Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber P, Bonaros EP Jr, Burashnikov E, Wu Y, Sargent JD, Schickel S, Oberheiden R, Bhatia A, Hsu LF, Haissaguerre M, Schimpf R, Borggrefe M, Wolpert C. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007;115:442–9.

    Article  PubMed  PubMed Central  Google Scholar 

  353. Ikram MA, Seshadri S, Bis JC, Fornage M, DeStefano AL, Aulchenko YS, Debette S, Lumley T, Folsom AR, van den Herik EG, Bos MJ, Beiser A, Cushman M, Launer LJ, Shahar E, Struchalin M, Du Y, Glazer NL, Rosamond WD, Rivadeneira F, Kelly-Hayes M, Lopez OL, Coresh J, Hofman A, DeCarli C, Heckbert SR, Koudstaal PJ, Yang Q, Smith NL, Kase CS, Rice K, Haritunians T, Roks G, de Kort PL, Taylor KD, de Lau LM, Oostra BA, Uitterlinden AG, Rotter JI, Boerwinkle E, Psaty BM, Mosley TH, van Duijn CM, Breteler MM, Longstreth WT Jr, Wolf PA. Genomewide association studies of stroke. N Engl J Med. 2009;360:1718–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  354. Lemmens R, Abboud S, Robberecht W, Vanhees L, Pandolfo M, Thijs V, Goris A. Variant on 9p21 strongly associates with coronary heart disease, but lacks association with common stroke. Eur J Hum Genet. 2009;17:1287–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  355. Madelaine R, Sloan SA, Huber N, Notwell JH, Leung LC, Skariah G, Halluin C, Pasca SP, Bejerano G, Krasnow MA, Barres BA, Mourrain P. MicroRNA-9 couples brain neurogenesis and angiogenesis. Cell Rep. 2017;20:1533–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  356. Dykstra-Aiello C, Jickling GC, Ander BP, Shroff N, Zhan X, Liu D, Hull H, Orantia M, Stamova BS, Sharp FR. Altered expression of long noncoding RNAs in blood after ischemic stroke and proximity to putative stroke risk loci. Stroke. 2016;47:2896–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  357. Chen YG, Satpathy AT, Chang HY. Gene regulation in the immune system by long noncoding RNAs. Nat Immunol. 2017;18:962–72.

    Article  CAS  PubMed  Google Scholar 

  358. Schmitt AM, Chang HY. Long noncoding RNAs in cancer pathways. Cancer Cell. 2016;29:452–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  359. Liu SJ, Horlbeck MA, Cho SW, Birk HS, Malatesta M, He D, Attenello FJ, Villalta JE, Cho MY, Chen Y, Mandegar MA, Olvera MP, Gilbert LA, Conklin BR, Chang HY, Weissman JS, Lim DA. CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells. Science. 2017;355

    Google Scholar 

  360. Wang T, Birsoy K, Hughes NW, Krupczak KM, Post Y, Wei JJ, Lander ES, Sabatini DM. Identification and characterization of essential genes in the human genome. Science. 2015;350:1096–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  361. Hart T, Chandrashekhar M, Aregger M, Steinhart Z, Brown KR, MacLeod G, Mis M, Zimmermann M, Fradet-Turcotte A, Sun S, Mero P, Dirks P, Sidhu S, Roth FP, Rissland OS, Durocher D, Angers S, Moffat J. High-resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities. Cell. 2015;163:1515–26.

    Article  CAS  PubMed  Google Scholar 

  362. Chi KR. The dark side of the human genome. Nature. 2016;538:275–7.

    Article  CAS  PubMed  Google Scholar 

  363. Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M, Jaffrey SR. m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature. 2016;537:369–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  364. Dowdy SF. Overcoming cellular barriers for RNA therapeutics. Nat Biotechnol. 2017;35:222–9.

    Article  CAS  PubMed  Google Scholar 

  365. Cox DBT, Gootenberg JS, Abudayyeh OO, Franklin B, Kellner MJ, Joung J, Zhang F. RNA editing with CRISPR-Cas13. Science. 2017;358:1019–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was funded by the University Hospital Munich and by the German Research Foundation (DFG) as part of the Collaborative Research Center CRC1123 “Atherosclerosis—Mechanisms and Networks of Novel Therapeutic Targets” (project B1). Part of this project was also funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, # 394237736).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lesca M. Holdt .

Editor information

Editors and Affiliations

Ethics declarations

Not applicable.

Disclosures

None.

Conflicts of Interest

There are no competing interests.

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Holdt, L.M., Kohlmaier, A., Teupser, D. (2019). Long Noncoding RNAs in Cardiovascular Disease. In: Erdmann, J., Moretti, A. (eds) Genetic Causes of Cardiac Disease. Cardiac and Vascular Biology, vol 7. Springer, Cham. https://doi.org/10.1007/978-3-030-27371-2_7

Download citation

Publish with us

Policies and ethics