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Gene regulation of mammalian long non-coding RNA


RNA polymerase II (Pol II) transcribes two classes of RNAs, protein-coding and non-protein-coding (ncRNA) genes. ncRNAs are also synthesized by RNA polymerases I and III (Pol I and III). In humans, the number of ncRNA genes exceeds more than twice that of protein-coding genes. However, the history of studying Pol II-synthesized ncRNA is relatively short. Since early 2000s, important biological and pathological functions of these ncRNA genes have begun to be discovered and intensively studied. And transcription mechanisms of long non-coding RNA (lncRNA) have been recently reported. Transcription of lncRNAs utilizes some transcription factors and mechanisms shared in that of protein-coding genes. In addition, tissue specificity in lncRNA gene expression has been shown. LncRNAs play essential roles in regulating the expression of neighboring or distal genes through different mechanisms. This leads to the implication of lncRNAs in a wide variety of biological pathways and pathological development. In this review, the newly discovered transcription mechanisms, characteristics, and functions of lncRNA are discussed.

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Fig. 1
Fig. 2
Fig. 3



Antisense non-coding RNA in the INK4 locus


Ataxia telangiectasia mutated


B-site APP cleaving enzyme-1


B-site APP cleaving enzyme-1- antisense transcript


Cardiac apoptosis-related lncRNA


CCCTC-binding factor


DNA methyltransferase 3


DNA-dependent protein kinase


DRB sensitivity-inducing factor


Enhancer RNA


Heat shock factor 1


Heat shock protein 70


Hox transcript antisense RNA


Human embryonic kidney 293


Long non-coding RNA


Metastasis-associated lung adenocarcinoma transcription 1


Mouse embryonic stem


Myocardial infarction associated transcript


Myosin heavy gene 7


Natural antisense transcript


Negative elongation factor


Non-coding RNA


Poly(A)-binding protein nuclear 1


Positive transcription elongation factor b

Pol II:

RNA polymerase II


Single nucleotide polymorphism


Transcription start site


Transcription termination site


Tripartite motif containing 28


X inactivate-specific transcript


XRN1 (5′ → 3′ exonuclease)-sensitive unstable transcript


  1. Adelman K, Lis JT (2012) Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat Rev Genet 13:720–731

  2. Aranda S, Mas G, Di Croce L (2015) Regulation of gene transcription by Polycomb proteins. Sci Adv 1:e1500737

  3. Beltran M, Puig I, Pena C, Garcia JM, Alvarez AB, Pena R, Bonilla F, de Herreros AG (2008) A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. Genes Dev 22:756–769

  4. Berghoff EG, Clark MF, Chen S, Cajigas I, Leib DE, Kohtz JD (2013) Evf2 (Dlx6as) lncRNA regulates ultraconserved enhancer methylation and the differential transcriptional control of adjacent genes. Development 140:4407–4416

  5. Blackledge NP, Farcas AM, Kondo T, King HW, McGouran JF, Hanssen LL, Ito S, Cooper S, Kondo K, Koseki Y, Ishikura T, Long HK, Sheahan TW, Brockdorff N, Kessler BM, Koseki H, Klose RJ (2014) Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation. Cell 157:1445–1459

  6. Blin N, Stephenson EC, Stafford DW (1976) Isolation and some properties of a mammalian ribosomal DNA. Chromosoma 58:41–50

  7. Blondeau JJ, Deng M, Syring I, Schrodter S, Schmidt D, Perner S, Muller SC, Ellinger J (2015) Identification of novel long non-coding RNAs in clear cell renal cell carcinoma. Clin Epigenetics 7:10

  8. Bloom GS (2014) Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71:505–508

  9. Braidotti G, Baubec T, Pauler F, Seidl C, Smrzka O, Stricker S, Yotova I, Barlow DP (2004) The Air noncoding RNA: an imprinted cis-silencing transcript. Cold Spring Harb Symp Quant Biol 69:55–66

  10. Brockdorff N (2013) Noncoding RNA and Polycomb recruitment. RNA 19:429–442

  11. Brockdorff N, Ashworth A, Kay GF, McCabe VM, Norris DP, Cooper PJ, Swift S, Rastan S (1992) The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71:515–526

  12. Brown CJ, Hendrich BD, Rupert JL, Lafreniere RG, Xing Y, Lawrence J, Willard HF (1992) The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71:527–542

  13. Brown SA, Imbalzano AN, Kingston RE (1996) Activator-dependent regulation of transcriptional pausing on nucleosomal templates. Genes Dev 10:1479–1490

  14. Buckley MS, Kwak H, Zipfel WR, Lis JT (2014) Kinetics of promoter Pol II on Hsp70 reveal stable pausing and key insights into its regulation. Genes Dev 28:14–19

  15. Bunch H (2016) Role of genome guardian proteins in transcriptional elongation. FEBS Lett 590:1064–1075

  16. Bunch H, Calderwood SK (2015) TRIM28 as a novel transcriptional elongation factor. BMC Mol Biol 16:14

  17. Bunch H, Zheng X, Burkholder A, Dillon ST, Motola S, Birrane G, Ebmeier CC, Levine S, Fargo D, Hu G, Taatjes DJ, Calderwood SK (2014) TRIM28 regulates RNA polymerase II promoter-proximal pausing and pause release. Nat Struct Mol Biol 21:876–883

  18. Bunch H, Lawney BP, Lin YF, Asaithamby A, Murshid A, Wang YE, Chen BP, Calderwood SK (2015) Transcriptional elongation requires DNA break-induced signalling. Nat Commun 6:10191

  19. Bunch H, Lawney BP, Burkholder A, Ma D, Zheng X, Motola S, Fargo DC, Levine SS, Wang YE, Hu G (2016) RNA polymerase II promoter-proximal pausing in mammalian long non-coding genes. Genomics 108:64–77

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

  21. Calderwood SK, Xie Y, Wang X, Khaleque MA, Chou SD, Murshid A, Prince T, Zhang Y (2010) Signal transduction pathways leading to heat shock transcription. Signal Transduct Insights 2:13–24

  22. Cao J (2014) The functional role of long non-coding RNAs and epigenetics. Biol Proced Online 16:11

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

  24. 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 (2012) Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature 491:454–457

  25. Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, Tramontano A, Bozzoni I (2011) A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147:358–369

  26. Chase A, Cross NC (2011) Aberrations of EZH2 in cancer. Clin Cancer Res 17:2613–2618

  27. Chen X, Yan CC, Zhang X, You ZH (2016a) Long non-coding RNAs and complex diseases: from experimental results to computational models. Brief Bioinform 2016:bbw060

  28. Chen Z, Liu Y, He A, Li J, Chen M, Zhan Y, Lin J, Zhuang C, Liu L, Zhao G, Huang W, Cai Z (2016b) Theophylline controllable RNAi-based genetic switches regulate expression of lncRNA TINCR and malignant phenotypes in bladder cancer cells. Sci Rep 6:30798

  29. Cheng C, Sharp PA (2003) RNA polymerase II accumulation in the promoter-proximal region of the dihydrofolate reductase and gamma-actin genes. Mol Cell Biol 23:1961–1967

  30. Clark MB, Mercer TR, Bussotti G, Leonardi T, Haynes KR, Crawford J, Brunck ME, Cao KA, Thomas GP, Chen WY, Taft RJ, Nielsen LK, Enright AJ, Mattick JS, Dinger ME (2015) Quantitative gene profiling of long noncoding RNAs with targeted RNA sequencing. Nat Methods 12:339–342

  31. Cole SL, Vassar R (2007) The Alzheimer’s disease beta-secretase enzyme, BACE1. Mol Neurodegener 2:22

  32. Core LJ, Waterfall JJ, Lis JT (2008) Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322:1845–1848

  33. Core LJ, Waterfall JJ, Gilchrist DA, Fargo DC, Kwak H, Adelman K, Lis JT (2012) Defining the status of RNA polymerase at promoters. Cell Rep 2:1025–1035

  34. Dai W, Zhang G, Makeyev EV (2012) RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage. Nucleic Acids Res 40:787–800

  35. Davidovich C, Zheng L, Goodrich KJ, Cech TR (2013) Promiscuous RNA binding by Polycomb repressive complex 2. Nat Struct Mol Biol 20:1250–1257

  36. Dey BK, Pfeifer K, Dutta A (2014) The H19 long noncoding RNA gives rise to microRNAs miR-675-3p and miR-675-5p to promote skeletal muscle differentiation and regeneration. Genes Dev 28:491–501

  37. Dong X, Chen K, Cuevas-Diaz Duran R, You Y, Sloan SA, Zhang Y, Zong S, Cao Q, Barres BA, Wu JQ (2015) Comprehensive identification of long non-coding RNAs in purified cell types from the brain reveals functional LncRNA in OPC fate determination. PLoS Genet 11:e1005669

  38. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, Waghorn K, Zoi K, Ross FM, Reiter A, Hochhaus A, Drexler HG, Duncombe A, Cervantes F, Oscier D, Boultwood J, Grand FH, Cross NC (2010) Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 42:722–726

  39. Espinoza CA, Allen TA, Hieb AR, Kugel JF, Goodrich JA (2004) B2 RNA binds directly to RNA polymerase II to repress transcript synthesis. Nat Struct Mol Biol 11:822–829

  40. Esteller M (2011) Non-coding RNAs in human disease. Nat Rev Genet 12:861–874

  41. Faghihi MA, Zhang M, Huang J, Modarresi F, Van der Brug MP, Nalls MA, Cookson MR, St-Laurent G 3rd, Wahlestedt C (2010) Evidence for natural antisense transcript-mediated inhibition of microRNA function. Genome Biol 11:R56

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

  43. Feng J, Bi C, Clark BS, Mady R, Shah P, Kohtz JD (2006) The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes Dev 20:1470–1484

  44. Fuda NJ, Guertin MJ, Sharma S, Danko CG, Martins AL, Siepel A, Lis JT (2015) GAGA factor maintains nucleosome-free regions and has a role in RNA polymerase II recruitment to promoters. PLoS Genet 11:e1005108

  45. Gallagher PG (2014) Long noncoding RNAs in erythropoiesis. Blood 123:465–466

  46. Gao P, Wei GH (2017) Genomic insight into the role of lncRNA in cancer susceptibility. Int J Mol Sci 18:E1239

  47. Geisler S, Coller J (2013) RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat Rev Mol Cell Biol 14:699–712

  48. Geisler S, Lojek L, Khalil AM, Baker KE, Coller J (2012) Decapping of long noncoding RNAs regulates inducible genes. Mol Cell 45:279–291

  49. Gilbert SL, Pehrson JR, Sharp PA (2000) XIST RNA associates with specific regions of the inactive X chromatin. J Biol Chem 275:36491–36494

  50. Gilchrist DA, Dos Santos G, Fargo DC, Xie B, Gao Y, Li L, Adelman K (2010) Pausing of RNA polymerase II disrupts DNA-specified nucleosome organization to enable precise gene regulation. Cell 143:540–551

  51. Glover-Cutter K, Kim S, Espinosa J, Bentley DL (2008) RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes. Nat Struct Mol Biol 15:71–78

  52. Golding MC, Magri LS, Zhang L, Lalone SA, Higgins MJ, Mann MR (2011) Depletion of Kcnq1ot1 non-coding RNA does not affect imprinting maintenance in stem cells. Development 138:3667–3678

  53. Gonzalez J, Qi H, Liu N, Lin H (2015) Piwi is a key regulator of both somatic and germline stem cells in the Drosophila testis. Cell Rep 12:150–161

  54. Guil S, Esteller M (2012) Cis-acting noncoding RNAs: friends and foes. Nat Struct Mol Biol 19:1068–1075

  55. Guo H, Ahmed M, Zhang F, Yao CQ, Li S, Liang Y, Hua J, Soares F, Sun Y, Langstein J, Li Y, Poon C, Bailey SD, Desai K, Fei T, Li Q, Sendorek DH, Fraser M, Prensner JR, Pugh TJ, Pomerantz M, Bristow RG, Lupien M, Feng FY, Boutros PC, Freedman ML, Walsh MJ, He HH (2016) Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer. Nat Genet 48:1142–1150

  56. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S, Chang HY (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464:1071–1076

  57. Hajjari M, Salavaty A (2015) HOTAIR: an oncogenic long non-coding RNA in different cancers. Cancer Biol Med 12:1–9

  58. 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 (2014) A long noncoding RNA protects the heart from pathological hypertrophy. Nature 514:102–106

  59. Harr JC, Gonzalez-Sandoval A, Gasser SM (2016) Histones and histone modifications in perinuclear chromatin anchoring: from yeast to man. EMBO Rep 17:139–155

  60. Hauptman N, Glavac D (2013) Long non-coding RNA in cancer. Int J Mol Sci 14:4655–4669

  61. Hazra J, Mukherjee P, Ali A, Poddar S, Pal M (2017) Engagement of components of DNA-break repair complex and NFkappaB in Hsp70A1A transcription upregulation by heat shock. PLoS One 12:e0168165

  62. Huang JF, Guo YJ, Zhao CX, Yuan SX, Wang Y, Tang GN, Zhou WP, Sun SH (2013) Hepatitis B virus X protein (HBx)-related long noncoding RNA (lncRNA) down-regulated expression by HBx (Dreh) inhibits hepatocellular carcinoma metastasis by targeting the intermediate filament protein vimentin. Hepatology 57:1882–1892

  63. Huang YS, Chang CC, Lee SS, Jou YS, Shih HM (2016) Xist reduction in breast cancer upregulates AKT phosphorylation via HDAC3-mediated repression of PHLPP1 expression. Oncotarget 7:43256–43266

  64. Hussain S, Feldman AL, Das C, Ziesmer SC, Ansell SM, Galardy PJ (2013) Ubiquitin hydrolase UCH-L1 destabilizes mTOR complex 1 by antagonizing DDB1-CUL4-mediated ubiquitination of raptor. Mol Cell Biol 33:1188–1197

  65. International Human Genome Sequencing C (2004) Finishing the euchromatic sequence of the human genome. Nature 431:931–945

  66. Ishibashi M, Kogo R, Shibata K, Sawada G, Takahashi Y, Kurashige J, Akiyoshi S, Sasaki S, Iwaya T, Sudo T, Sugimachi K, Mimori K, Wakabayashi G, Mori M (2013) Clinical significance of the expression of long non-coding RNA HOTAIR in primary hepatocellular carcinoma. Oncol Rep 29:946–950

  67. Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, Barrette TR, Prensner JR, Evans JR, Zhao S, Poliakov A, Cao X, Dhanasekaran SM, Wu YM, Robinson DR, Beer DG, Feng FY, Iyer HK, Chinnaiyan AM (2015) The landscape of long noncoding RNAs in the human transcriptome. Nat Genet 47:199–208

  68. Jackson RJ, Hellen CU, Pestova TV (2010) The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol 11:113–127

  69. Jiang C, Li Y, Zhao Z, Lu J, Chen H, Ding N, Wang G, Xu J, Li X (2016) Identifying and functionally characterizing tissue-specific and ubiquitously expressed human lncRNAs. Oncotarget 7:7120–7133

  70. Johnson R (2012) Long non-coding RNAs in Huntington’s disease neurodegeneration. Neurobiol Dis 46:245–254

  71. Johnson R, Teh CH, Jia H, Vanisri RR, Pandey T, Lu ZH, Buckley NJ, Stanton LW, Lipovich L (2009) Regulation of neural macroRNAs by the transcriptional repressor REST. RNA 15:85–96

  72. Karapetyan AR, Buiting C, Kuiper RA, Coolen MW (2013) Regulatory roles for long ncRNA and mRNA. Cancers (Basel) 5:462–490

  73. Keniry A, Oxley D, Monnier P, Kyba M, Dandolo L, Smits G, Reik W (2012) The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r. Nat Cell Biol 14:659–665

  74. Kornienko AE, Dotter CP, Guenzl PM, Gisslinger H, Gisslinger B, Cleary C, Kralovics R, Pauler FM, Barlow DP (2016) Long non-coding RNAs display higher natural expression variation than protein-coding genes in healthy humans. Genome Biol 17:14

  75. Kotake Y, Nakagawa T, Kitagawa K, Suzuki S, Liu N, Kitagawa M, Xiong Y (2011) Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene 30:1956–1962

  76. Kretz M, Siprashvili Z, Chu C, Webster DE, Zehnder A, Qu K, Lee CS, Flockhart RJ, Groff AF, Chow J, Johnston D, Kim GE, Spitale RC, Flynn RA, Zheng GX, Aiyer S, Raj A, Rinn JL, Chang HY, Khavari PA (2013) Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature 493:231–235

  77. Kumar V, Westra HJ, Karjalainen J, Zhernakova DV, Esko T, Hrdlickova B, Almeida R, Zhernakova A, Reinmaa E, Vosa U, Hofker MH, Fehrmann RS, Fu J, Withoff S, Metspalu A, Franke L, Wijmenga C (2013) Human disease-associated genetic variation impacts large intergenic non-coding RNA expression. PLoS Genet 9:e1003201

  78. Kupper H, Sekiya T, Rosenberg M, Egan J, Landy A (1978) A rho-dependent termination site in the gene coding for tyrosine tRNA su3 of Escherichia coli. Nature 272:423–428

  79. Lagha M, Bothma JP, Esposito E, Ng S, Stefanik L, Tsui C, Johnston J, Chen K, Gilmour DS, Zeitlinger J, Levine MS (2013) Paused Pol II coordinates tissue morphogenesis in the Drosophila embryo. Cell 153:976–987

  80. Lee JT, Bartolomei MS (2013) X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell 152:1308–1323

  81. Lee TI, Young RA (2013) Transcriptional regulation and its misregulation in disease. Cell 152:1237–1251

  82. Lee C, Li X, Hechmer A, Eisen M, Biggin MD, Venters BJ, Jiang C, Li J, Pugh BF, Gilmour DS (2008) NELF and GAGA factor are linked to promoter-proximal pausing at many genes in Drosophila. Mol Cell Biol 28:3290–3300

  83. Lee JH, Gao C, Peng G, Greer C, Ren S, Wang Y, Xiao X (2011) Analysis of transcriptome complexity through RNA sequencing in normal and failing murine hearts. Circ Res 109:1332–1341

  84. Legnini I, Morlando M, Mangiavacchi A, Fatica A, Bozzoni I (2014) A feedforward regulatory loop between HuR and the long noncoding RNA linc-MD1 controls early phases of myogenesis. Mol Cell 53:506–514

  85. Levine M (2011) Paused RNA polymerase II as a developmental checkpoint. Cell 145:502–511

  86. Li B, Weber JA, Chen Y, Greenleaf AL, Gilmour DS (1996) Analyses of promoter-proximal pausing by RNA polymerase II on the hsp70 heat shock gene promoter in a Drosophila nuclear extract. Mol Cell Biol 16:5433–5443

  87. Li W, Zhai L, Wang H, Liu C, Zhang J, Chen W, Wei Q (2016a) Downregulation of LncRNA GAS5 causes trastuzumab resistance in breast cancer. Oncotarget 7:27778–27786

  88. Li X, Wang H, Yao B, Xu W, Chen J, Zhou X (2016b) lncRNA H19/miR-675 axis regulates cardiomyocyte apoptosis by targeting VDAC1 in diabetic cardiomyopathy. Sci Rep 6:36340

  89. Li Y, Wang Z, Shi H, Li H, Li L, Fang R, Cai X, Liu B, Zhang X, Ye L (2016c) HBXIP and LSD1 scaffolded by lncRNA hotair mediate transcriptional activation by c-Myc. Cancer Res 76:293–304

  90. Lis JT, Mason P, Peng J, Price DH, Werner J (2000) P-TEFb kinase recruitment and function at heat shock loci. Genes Dev 14:792–803

  91. Liu Y, Lu X (2012) Non-coding RNAs in DNA damage response. Am J Cancer Res 2:658–675

  92. Liu X, Kraus WL, Bai X (2015) Ready, pause, go: regulation of RNA polymerase II pausing and release by cellular signaling pathways. Trends Biochem Sci 40:516–525

  93. Llorens-Rico V, Cano J, Kamminga T, Gil R, Latorre A, Chen WH, Bork P, Glass JI, Serrano L, Lluch-Senar M (2016) Bacterial antisense RNAs are mainly the product of transcriptional noise. Sci Adv 2:e1501363

  94. Luo Q, Chen Y (2016) Long noncoding RNAs and Alzheimer’s disease. Clin Interv Aging 11:867–872

  95. Luo S, Lu JY, Liu L, Yin Y, Chen C, Han X, Wu B, Xu R, Liu W, Yan P, Shao W, Lu Z, Li H, Na J, Tang F, Wang J, Zhang YE, Shen X (2016) Divergent lncRNAs regulate gene expression and lineage differentiation in pluripotent cells. Cell Stem Cell 18:637–652

  96. Ma XY, Wang JH, Wang JL, Ma CX, Wang XC, Liu FS (2015) Malat1 as an evolutionarily conserved lncRNA, plays a positive role in regulating proliferation and maintaining undifferentiated status of early-stage hematopoietic cells. BMC Genom 16:676

  97. Madabhushi R, Gao F, Pfenning AR, Pan L, Yamakawa S, Seo J, Rueda R, Phan TX, Yamakawa H, Pao PC, Stott RT, Gjoneska E, Nott A, Cho S, Kellis M, Tsai LH (2015) Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell 161:1592–1605

  98. Matouk IJ, Raveh E, Abu-lail R, Mezan S, Gilon M, Gershtain E, Birman T, Gallula J, Schneider T, Barkali M, Richler C, Fellig Y, Sorin V, Hubert A, Hochberg A, Czerniak A (2014) Oncofetal H19 RNA promotes tumor metastasis. Biochim Biophys Acta 1843:1414–1426

  99. Maxwell CS, Kruesi WS, Core LJ, Kurhanewicz N, Waters CT, Lewarch CL, Antoshechkin I, Lis JT, Meyer BJ, Baugh LR (2014) Pol II docking and pausing at growth and stress genes in C. elegans. Cell Rep 6:455–466

  100. Mei Y, Si J, Wang Y, Huang Z, Zhu H, Feng S, Wu X, Wu L (2017) Long noncoding RNA GAS5 suppresses tumorigenesis by inhibiting miR-23a 5 expression in non-small cell lung cancer. Oncol Res 25:1027–1037

  101. Mercer TR, Qureshi IA, Gokhan S, Dinger ME, Li G, Mattick JS, Mehler MF (2010) Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation. BMC Neurosci 11:14

  102. Michalak P (2008) Coexpression, coregulation, and cofunctionality of neighboring genes in eukaryotic genomes. Genomics 91:243–248

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

  104. Morris KV, Mattick JS (2014) The rise of regulatory RNA. Nat Rev Genet 15:423–437

  105. Nechaev S, Fargo DC, dos Santos G, Liu L, Gao Y, Adelman K (2010) Global analysis of short RNAs reveals widespread promoter-proximal stalling and arrest of Pol II in Drosophila. Science 327:335–338

  106. Ng KW, Anderson C, Marshall EA, Minatel BC, Enfield KS, Saprunoff HL, Lam WL, Martinez VD (2016) Piwi-interacting RNAs in cancer: emerging functions and clinical utility. Mol Cancer 15:5

  107. Nie L, Wu HJ, Hsu JM, Chang SS, Labaff AM, Li CW, Wang Y, Hsu JL, Hung MC (2012) Long non-coding RNAs: versatile master regulators of gene expression and crucial players in cancer. Am J Transl Res 4:127–150

  108. Oner C, Turgut Cosan D, Colak E (2016) Estrogen and androgen hormone levels modulate the expression of PIWI interacting RNA in prostate and breast cancer. PLoS One 11:e0159044

  109. Orzan F, Pellegatta S, Poliani PL, Pisati F, Caldera V, Menghi F, Kapetis D, Marras C, Schiffer D, Finocchiaro G (2011) Enhancer of Zeste 2 (EZH2) is up-regulated in malignant gliomas and in glioma stem-like cells. Neuropathol Appl Neurobiol 37:381–394

  110. Ozaki K, Tanaka T (2016) Molecular genetics of coronary artery disease. J Hum Genet 61:71–77

  111. Palazzo AF, Gregory TR (2014) The case for junk DNA. PLoS Genet 10:e1004351

  112. Parasramka MA, Maji S, Matsuda A, Yan IK, Patel T (2016) Long non-coding RNAs as novel targets for therapy in hepatocellular carcinoma. Pharmacol Ther 161:67–78

  113. Pastori C, Wahlestedt C (2012) Involvement of long noncoding RNAs in diseases affecting the central nervous system. RNA Biol 9:860–870

  114. Pelechano V, Steinmetz LM (2013) Gene regulation by antisense transcription. Nat Rev Genet 14:880–893

  115. Peterlin BM, Brogie JE, Price DH (2012) 7SK snRNA: a noncoding RNA that plays a major role in regulating eukaryotic transcription. Wiley Interdiscip Rev RNA 3:92–103

  116. Petesch SJ, Lis JT (2008) Rapid, transcription-independent loss of nucleosomes over a large chromatin domain at Hsp70 loci. Cell 134:74–84

  117. Popov N, Gil J (2010) Epigenetic regulation of the INK4b–ARF–INK4a locus: in sickness and in health. Epigenetics 5:685–690

  118. Puc J, Kozbial P, Li W, Tan Y, Liu Z, Suter T, Ohgi KA, Zhang J, Aggarwal AK, Rosenfeld MG (2015) Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160:367–380

  119. Pullen TJ, Rutter GA (2014) Roles of lncRNAs in pancreatic beta cell identity and diabetes susceptibility. Front Genet 5:193

  120. 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 (2017) MIAT is a pro-fibrotic long non-coding RNA governing cardiac fibrosis in post-infarct myocardium. Sci Rep 7:42657

  121. Quinn JJ, Chang HY (2016) Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet 17:47–62

  122. Rackham O, Shearwood AM, Mercer TR, Davies SM, Mattick JS, Filipovska A (2011) Long noncoding RNAs are generated from the mitochondrial genome and regulated by nuclear-encoded proteins. RNA 17:2085–2093

  123. Rahl PB, Lin CY, Seila AC, Flynn RA, McCuine S, Burge CB, Sharp PA, Young RA (2010) c-Myc regulates transcriptional pause release. Cell 141:432–445

  124. Rashid F, Shah A, Shan G (2016) Long Non-coding RNAs in the Cytoplasm. Genom Proteom Bioinform 14:73–80

  125. Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem 81:145–166

  126. Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, Chang HY (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129:1311–1323

  127. Roberts TC, Wood MJ (2013) Therapeutic targeting of non-coding RNAs. Essays Biochem 54:127–145

  128. Ross RJ, Weiner MM, Lin H (2014) PIWI proteins and PIWI-interacting RNAs in the soma. Nature 505:353–359

  129. Sarachana T, Dahiya N, Simhadri VL, Pandey GS, Saini S, Guelcher C, Guerrera MF, Kimchi-Sarfaty C, Sauna ZE, Atreya CD (2015) Small ncRNA expression-profiling of blood from hemophilia A patients identifies miR-1246 as a potential regulator of factor 8 gene. PLoS One 10:e0132433

  130. Sarma K, Cifuentes-Rojas C, Ergun A, Del Rosario A, Jeon Y, White F, Sadreyev R, Lee JT (2014) ATRX directs binding of PRC2 to Xist RNA and Polycomb targets. Cell 159:869–883

  131. Shah S, Wittmann S, Kilchert C, Vasiljeva L (2014) lncRNA recruits RNAi and the exosome to dynamically regulate pho1 expression in response to phosphate levels in fission yeast. Genes Dev 28:231–244

  132. Signal B, Gloss BS, Dinger ME (2016) Computational approaches for functional prediction and characterisation of long noncoding RNAs. Trends Genet 32:620–637

  133. Sigova AA, Mullen AC, Molinie B, Gupta S, Orlando DA, Guenther MG, Almada AE, Lin C, Sharp PA, Giallourakis CC, Young RA (2013) Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells. Proc Natl Acad Sci USA 110:2876–2881

  134. Simons RW, Kleckner N (1988) Biological regulation by antisense RNA in prokaryotes. Annu Rev Genet 22:567–600

  135. Sims RJ 3rd, Belotserkovskaya R, Reinberg D (2004) Elongation by RNA polymerase II: the short and long of it. Genes Dev 18:2437–2468

  136. Sirchia SM, Tabano S, Monti L, Recalcati MP, Gariboldi M, Grati FR, Porta G, Finelli P, Radice P, Miozzo M (2009) Misbehaviour of XIST RNA in breast cancer cells. PLoS One 4:e5559

  137. Soreq L, Guffanti A, Salomonis N, Simchovitz A, Israel Z, Bergman H, Soreq H (2014) Long non-coding RNA and alternative splicing modulations in Parkinson’s leukocytes identified by RNA sequencing. PLoS Comput Biol 10:e1003517

  138. Srikantan V, Zou Z, Petrovics G, Xu L, Augustus M, Davis L, Livezey JR, Connell T, Sesterhenn IA, Yoshino K, Buzard GS, Mostofi FK, McLeod DG, Moul JW, Srivastava S (2000) PCGEM1, a prostate-specific gene, is overexpressed in prostate cancer. Proc Natl Acad Sci USA 97:12216–12221

  139. Struhl K (2007) Transcriptional noise and the fidelity of initiation by RNA polymerase II. Nat Struct Mol Biol 14:103–105

  140. Sun S, Del Rosario BC, Szanto A, Ogawa Y, Jeon Y, Lee JT (2013) Jpx RNA activates Xist by evicting CTCF. Cell 153:1537–1551

  141. Sun M, Jin FY, Xia R, Kong R, Li JH, Xu TP, Liu YW, Zhang EB, Liu XH, De W (2014) Decreased expression of long noncoding RNA GAS5 indicates a poor prognosis and promotes cell proliferation in gastric cancer. BMC Cancer 14:319

  142. Sun M, Gadad SS, Kim DS, Kraus WL (2015) Discovery, annotation, and functional analysis of long noncoding RNAs controlling cell-cycle gene expression and proliferation in breast cancer cells. Mol Cell 59:698–711

  143. Tripathi V, Shen Z, Chakraborty A, Giri S, Freier SM, Wu X, Zhang Y, Gorospe M, Prasanth SG, Lal A, Prasanth KV (2013) Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB. PLoS Genet 9:e1003368

  144. Tsoi LC, Iyer MK, Stuart PE, Swindell WR, Gudjonsson JE, Tejasvi T, Sarkar MK, Li B, Ding J, Voorhees JJ, Kang HM, Nair RP, Chinnaiyan AM, Abecasis GR, Elder JT (2015) Analysis of long non-coding RNAs highlights tissue-specific expression patterns and epigenetic profiles in normal and psoriatic skin. Genome Biol 16:24

  145. Uchida S, Dimmeler S (2015) Long noncoding RNAs in cardiovascular diseases. Circ Res 116:737–750

  146. Uesaka M, Nishimura O, Go Y, Nakashima K, Agata K, Imamura T (2014) Bidirectional promoters are the major source of gene activation-associated non-coding RNAs in mammals. BMC Genom 15:35

  147. van Dijk EL, Chen CL, d’Aubenton-Carafa Y, Gourvennec S, Kwapisz M, Roche V, Bertrand C, Silvain M, Legoix-Ne P, Loeillet S, Nicolas A, Thermes C, Morillon A (2011) XUTs are a class of Xrn1-sensitive antisense regulatory non-coding RNA in yeast. Nature 475:114–117

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

  149. Vausort M, Wagner DR, Devaux Y (2014) Long noncoding RNAs in patients with acute myocardial infarction. Circ Res 115:668–677

  150. Vucicevic D, Corradin O, Ntini E, Scacheri PC, Orom UA (2015) Long ncRNA expression associates with tissue-specific enhancers. Cell Cycle 14:253–260

  151. Wada T, Takagi T, Yamaguchi Y, Ferdous A, Imai T, Hirose S, Sugimoto S, Yano K, Hartzog GA, Winston F, Buratowski S, Handa H (1998) DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs. Genes Dev 12:343–356

  152. Wang J, Liu X, Wu H, Ni P, Gu Z, Qiao Y, Chen N, Sun F, Fan Q (2010) CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nucleic Acids Res 38:5366–5383

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

  154. Wang Y, Liu XJ, Yao XD (2014b) Function of PCA3 in prostate tissue and clinical research progress on developing a PCA3 score. Chin J Cancer Res 26:493–500

  155. Wang K, Liu CY, Zhou LY, Wang JX, Wang M, Zhao B, Zhao WK, Xu SJ, Fan LH, Zhang XJ, Feng C, Wang CQ, Zhao YF, Li PF (2015) APF lncRNA regulates autophagy and myocardial infarction by targeting miR-188-3p. Nat Commun 6:6779

  156. Wang J, Geng Z, Weng J, Shen L, Li M, Cai X, Sun C, Chu M (2016a) Microarray analysis reveals a potential role of LncRNAs expression in cardiac cell proliferation. BMC Dev Biol 16:41

  157. Wang SH, Zhang WJ, Wu XC, Weng MZ, Zhang MD, Cai Q, Zhou D, Wang JD, Quan ZW (2016b) The lncRNA MALAT1 functions as a competing endogenous RNA to regulate MCL-1 expression by sponging miR-363-3p in gallbladder cancer. J Cell Mol Med 20:2299–2308

  158. Wight M, Werner A (2013) The functions of natural antisense transcripts. Essays Biochem 54:91–101

  159. Wu X, Sharp PA (2013) Divergent transcription: a driving force for new gene origination? Cell 155:990–996

  160. Wu W, Wagner EK, Hao Y, Rao X, Dai H, Han J, Chen J, Storniolo AM, Liu Y, He C (2016) Tissue-specific co-expression of long non-coding and coding RNAs associated with breast cancer. Sci Rep 6:32731

  161. Wutz A, Jaenisch R (2000) A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. Mol Cell 5:695–705

  162. Yan C, Zhang D, Raygoza Garay JA, Mwangi MM, Bai L (2015) Decoupling of divergent gene regulation by sequence-specific DNA binding factors. Nucleic Acids Res 43:7292–7305

  163. Yan C, Wu S, Pocetti C, Bai L (2016) Regulation of cell-to-cell variability in divergent gene expression. Nat Commun 7:11099

  164. Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT, Lee JT (2013) Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 152:727–742

  165. Yoon YJ, Kim JA, Shin KD, Shin DS, Han YM, Lee YJ, Lee JS, Kwon BM, Han DC (2011) KRIBB11 inhibits HSP70 synthesis through inhibition of heat shock factor 1 function by impairing the recruitment of positive transcription elongation factor b to the hsp70 promoter. J Biol Chem 286:1737–1747

  166. Yoon JH, Abdelmohsen K, Srikantan S, Yang X, Martindale JL, De S, Huarte M, Zhan M, Becker KG, Gorospe M (2012) LincRNA-p21 suppresses target mRNA translation. Mol Cell 47:648–655

  167. Young RA (1991) RNA polymerase II. Annu Rev Biochem 60:689–715

  168. Zhang Y, Liu XS, Liu QR, Wei L (2006) Genome-wide in silico identification and analysis of cis natural antisense transcripts (cis-NATs) in ten species. Nucleic Acids Res 34:3465–3475

  169. Zhang EB, Yin DD, Sun M, Kong R, Liu XH, You LH, Han L, Xia R, Wang KM, Yang JS, De W, Shu YQ, Wang ZX (2014a) P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression. Cell Death Dis 5:e1243

  170. Zhang XO, Yin QF, Chen LL, Yang L (2014b) Gene expression profiling of non-polyadenylated RNA-seq across species. Genom Data 2:237–241

  171. Zheng J, Huang X, Tan W, Yu D, Du Z, Chang J, Wei L, Han Y, Wang C, Che X, Zhou Y, Miao X, Jiang G, Yu X, Yang X, Cao G, Zuo C, Li Z, Wang C, Cheung ST, Jia Y, Zheng X, Shen H, Wu C, Lin D (2016) Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation. Nat Genet 48:747–757

  172. Zhou J, Yang L, Zhong T, Mueller M, Men Y, Zhang N, Xie J, Giang K, Chung H, Sun X, Lu L, Carmichael GG, Taylor HS, Huang Y (2015) H19 lncRNA alters DNA methylation genome wide by regulating S-adenosylhomocysteine hydrolase. Nat Commun 6:10221

  173. Zobeck KL, Buckley MS, Zipfel WR, Lis JT (2010) Recruitment timing and dynamics of transcription factors at the Hsp70 loci in living cells. Mol Cell 40:965–975

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I appreciate my colleagues in the School of Applied Biosciences at Kyungpook National University, D. Taatjes at the University of Colorado, J. Roberts at Cornell University, G. Hu at National Institute of Environmental Health Sciences (NIEHS), and B. Chen and M. Story at the University of Texas Southwestern Medical Center for their support. I thank D. Bunch and R. Baker for their loving encouragement. I also thank Enago for the help with editing manuscript.

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Correspondence to Heeyoun Bunch.

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This study was supported by Grants from the Industry-Academic Cooperation Foundation at Kyungpook National University (KNU) to H.B.

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There is no conflict of interest for the enclosed review article.

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Communicated by S. Hohmann.

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Bunch, H. Gene regulation of mammalian long non-coding RNA. Mol Genet Genomics 293, 1–15 (2018). https://doi.org/10.1007/s00438-017-1370-9

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  • Long non-coding RNA
  • Transcriptional mechanism
  • Gene expression regulation