Long Non-Coding RNA-Mediated Regulation of the Interferon Response: A New Perspective on a Familiar Theme

Main Article Content

Saba Valadkhan
Leah M. Plasek

Abstract

The interferon (IFN) response is a critical and ubiquitous component of the innate immune response to pathogens. Detailed studies in the last decades have elucidated the function of a large number of proteins that mediate the complex signaling pathways and gene expression programs involved in the interferon response. The recent discovery of the long non-coding RNAs (lncRNAs) as a new category of cellular effectors has led to studies aiming to understand the role of these transcripts in the IFN response. Several high throughput studies have shown that a large number of lncRNAs are differentially expressed following IFN stimulation and/or viral infections. In-depth study of a very small fraction of the identified lncRNAs has revealed critical roles for this class of transcripts in the regulation of multiple steps of the IFN response, and pointed to the presence of an extensive RNA-mediated regulatory network during the antiviral response. As the vast majority of the identified potential regulatory lncRNAs remain unstudied, it is highly likely that future studies will reveal a completely new perspective on the regulation of the IFN response, with lncRNA- and protein-mediated regulatory networks coordinating the duration, magnitude, and character of this aspect of the innate immune response. In addition to providing a more complete picture of the IFN response, these studies will likely identify new therapeutic targets that in the long term may impact the therapeutic options available against microbial infections and diseases of the immune system.

Downloads

Download data is not yet available.

Article Details

Section
Reviews

References

1. Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14(1):36-49. PubMed PMID: 24362405. Pubmed Central PMCID: 4084561. doi: 10.1038/nri3581

2. Kotenko SV, Durbin JE. Contribution of type III interferons to antiviral immunity: location, location, location. J Biol Chem. 2017;292(18):7295-303. PubMed PMID: 28289095. Pubmed Central PMCID: 5418032. doi: 10.1074/jbc.R117.777102

3. Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, Langer JA, Sheikh F, Dickensheets H, Donnelly RP. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003;4(1):69-77. PubMed PMID: 12483210. doi: 10.1038/ni875

4. Lu YF, Goldstein DB, Urban TJ, Bradrick SS. Interferon-lambda4 is a cell-autonomous type III interferon associated with pre-treatment hepatitis C virus burden. Virology. 2015;476:334-40. PubMed PMID: 25577150. Pubmed Central PMCID: 4494652. doi: 10.1016/j.virol.2014.12.020

5. Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, Kuestner R, Garrigues U, Birks C, Roraback J, Ostrander C, Dong D, Shin J, Presnell S, Fox B, Haldeman B, Cooper E, Taft D, Gilbert T, Grant FJ, Tackett M, Krivan W, McKnight G, Clegg C, Foster D, Klucher KM. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol. 2003;4(1):63-8. PubMed PMID: 12469119. doi: 10.1038/ni873

6. Sommereyns C, Paul S, Staeheli P, Michiels T. IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog. 2008;4(3):e1000017. PubMed PMID: 18369468. Pubmed Central PMCID: 2265414. doi: 10.1371/journal.ppat.1000017

7. Hertzog PJ, Williams BR. Fine tuning type I interferon responses. Cytokine Growth Factor Rev. 2013;24(3):217-25. PubMed PMID: 23711406. doi: 10.1016/j.cytogfr.2013.04.002

8. Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol. 2014;32:513-45. PubMed PMID: 24555472. Pubmed Central PMCID: 4313732. doi: 10.1146/annurev-immunol-032713-120231

9. Kowalinski E, Lunardi T, McCarthy AA, Louber J, Brunel J, Grigorov B, Gerlier D, Cusack S. Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA. Cell. 2011;147(2):423-35. PubMed PMID: 22000019. doi: 10.1016/j.cell.2011.09.039

10. Hiscott J. Triggering the innate antiviral response through IRF-3 activation. J Biol Chem. 2007;282(21):15325-9. PubMed PMID: 17395583. doi: 10.1074/jbc.R700002200

11. Jensen S, Thomsen AR. Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion. J Virol. 2012;86(6):2900-10. PubMed PMID: 22258243. Pubmed Central PMCID: 3302314. doi: 10.1128/JVI.05738-11

12. Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol. 2006;7(2):131-7. PubMed PMID: 16424890. doi: 10.1038/ni1303

13. Onomoto K, Onoguchi K, Takahasi K, Fujita T. Type I interferon production induced by RIG-I-like receptors. J Interferon Cytokine Res. 2010;30(12):875-81. PubMed PMID: 21121861. doi: 10.1089/jir.2010.0117

14. Randall RE, Goodbourn S. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol. 2008;89(Pt 1):1-47. PubMed PMID: 18089727. doi: 10.1099/vir.0.83391-0

15. Takeuchi O, Akira S. Innate immunity to virus infection. Immunol Rev. 2009;227(1):75-86. PubMed PMID: 19120477. Pubmed Central PMCID: 5489343. doi: 10.1111/j.1600-065X.2008.00737.x

16. Keating SE, Baran M, Bowie AG. Cytosolic DNA sensors regulating type I interferon induction. Trends Immunol. 2011;32(12):574-81. PubMed PMID: 21940216. doi: 10.1016/j.it.2011.08.004

17. Paludan SR, Bowie AG. Immune sensing of DNA. Immunity. 2013;38(5):870-80. PubMed PMID: 23706668. Pubmed Central PMCID: 3683625. doi: 10.1016/j.immuni.2013.05.004

18. Kim MJ, Hwang SY, Imaizumi T, Yoo JY. Negative feedback regulation of RIG-I-mediated antiviral signaling by interferon-induced ISG15 conjugation. J Virol. 2008;82(3):1474-83. PubMed PMID: 18057259. Pubmed Central PMCID: 2224411. doi: 10.1128/JVI.01650-07

19. Deveson IW, Hardwick SA, Mercer TR, Mattick JS. The Dimensions, Dynamics, and Relevance of the Mammalian Noncoding Transcriptome. Trends Genet. 2017;33(7):464-78. PubMed PMID: 28535931. doi: 10.1016/j.tig.2017.04.004

20. Morris KV, Mattick JS. The rise of regulatory RNA. Nat Rev Genet. 2014;15(6):423-37. PubMed PMID: 24776770. Pubmed Central PMCID: 4314111. doi: 10.1038/nrg3722

21. Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet. 2016;17(1):47-62. PubMed PMID: 26666209. doi: 10.1038/nrg.2015.10

22. Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem. 2012;81:145-66. PubMed PMID: 22663078. Pubmed Central PMCID: 3858397. doi: 10.1146/annurev-biochem-051410-092902

23. Hube F, Francastel C. Coding and Non-coding RNAs, the Frontier Has Never Been So Blurred. Front Genet. 2018;9:140. PubMed PMID: 29720998. Pubmed Central PMCID: 5915474. doi: 10.3389/fgene.2018.00140

24. Ulveling D, Francastel C, Hube F. When one is better than two: RNA with dual functions. Biochimie. 2011;93(4):633-44. PubMed PMID: 21111023. doi: 10.1016/j.biochi.2010.11.004

25. Clark MB, Mattick JS. Long noncoding RNAs in cell biology. Semin Cell Dev Biol. 2011;22(4):366-76. PubMed PMID: 21256239. doi: 10.1016/j.semcdb.2011.01.001

26. Mattick JS, Rinn JL. Discovery and annotation of long noncoding RNAs. Nat Struct Mol Biol. 2015;22(1):5-7. PubMed PMID: 25565026. doi: 10.1038/nsmb.2942

27. Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi T, Lenhard B, Wells C, Kodzius R, Shimokawa K, Bajic VB, Brenner SE, Batalov S, Forrest AR, Zavolan M, Davis MJ, Wilming LG, Aidinis V, Allen JE, Ambesi-Impiombato A, Apweiler R, Aturaliya RN, Bailey TL, Bansal M, Baxter L, Beisel KW, Bersano T, Bono H, Chalk AM, Chiu KP, Choudhary V, Christoffels A, Clutterbuck DR, Crowe ML, Dalla E, Dalrymple BP, de Bono B, Della Gatta G, di Bernardo D, Down T, Engstrom P, Fagiolini M, Faulkner G, Fletcher CF, Fukushima T, Furuno M, Futaki S, Gariboldi M, Georgii-Hemming P, Gingeras TR, Gojobori T, Green RE, Gustincich S, Harbers M, Hayashi Y, Hensch TK, Hirokawa N, Hill D, Huminiecki L, Iacono M, Ikeo K, Iwama A, Ishikawa T, Jakt M, Kanapin A, Katoh M, Kawasawa Y, Kelso J, Kitamura H, Kitano H, Kollias G, Krishnan SP, Kruger A, Kummerfeld SK, Kurochkin IV, Lareau LF, Lazarevic D, Lipovich L, Liu J, Liuni S, McWilliam S, Madan Babu M, Madera M, Marchionni L, Matsuda H, Matsuzawa S, Miki H, Mignone F, Miyake S, Morris K, Mottagui-Tabar S, Mulder N, Nakano N, Nakauchi H, Ng P, Nilsson R, Nishiguchi S, Nishikawa S, Nori F, Ohara O, Okazaki Y, Orlando V, Pang KC, Pavan WJ, Pavesi G, Pesole G, Petrovsky N, Piazza S, Reed J, Reid JF, Ring BZ, Ringwald M, Rost B, Ruan Y, Salzberg SL, Sandelin A, Schneider C, Schonbach C, Sekiguchi K, Semple CA, Seno S, Sessa L, Sheng Y, Shibata Y, Shimada H, Shimada K, Silva D, Sinclair B, Sperling S, Stupka E, Sugiura K, Sultana R, Takenaka Y, Taki K, Tammoja K, Tan SL, Tang S, Taylor MS, Tegner J, Teichmann SA, Ueda HR, van Nimwegen E, Verardo R, Wei CL, Yagi K, Yamanishi H, Zabarovsky E, Zhu S, Zimmer A, Hide W, Bult C, Grimmond SM, Teasdale RD, Liu ET, Brusic V, Quackenbush J, Wahlestedt C, Mattick JS, Hume DA, Kai C, Sasaki D, Tomaru Y, Fukuda S, Kanamori-Katayama M, Suzuki M, Aoki J, Arakawa T, Iida J, Imamura K, Itoh M, Kato T, Kawaji H, Kawagashira N, Kawashima T, Kojima M, Kondo S, Konno H, Nakano K, Ninomiya N, Nishio T, Okada M, Plessy C, Shibata K, Shiraki T, Suzuki S, Tagami M, Waki K, Watahiki A, Okamura-Oho Y, Suzuki H, Kawai J, Hayashizaki Y, Consortium F, Group RGER, Genome Science G. The transcriptional landscape of the mammalian genome. Science. 2005;309(5740):1559-63. PubMed PMID: 16141072. doi: 10.1126/science.1112014

28. 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(9):1775-89. PubMed PMID: 22955988. Pubmed Central PMCID: 3431493. doi: 10.1101/gr.132159.111

29. 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(7414):101-8. PubMed PMID: 22955620. Pubmed Central PMCID: 3684276. doi: 10.1038/nature11233

30. Niazi F, Valadkhan S. Computational analysis of functional long noncoding RNAs reveals lack of peptide-coding capacity and parallels with 3' UTRs. RNA. 2012;18(4):825-43. PubMed PMID: 22361292. Pubmed Central PMCID: 3312569. 10.1261/rna.029520.111

31. Mele M, Mattioli K, Mallard W, Shechner DM, Gerhardinger C, Rinn JL. Chromatin environment, transcriptional regulation, and splicing distinguish lincRNAs and mRNAs. Genome Res. 2017;27(1):27-37. PubMed PMID: 27927715. Pubmed Central PMCID: 5204342. doi: 10.1101/gr.214205.116

32. Amaral PP, Dinger ME, Mattick JS. Non-coding RNAs in homeostasis, disease and stress responses: an evolutionary perspective. Brief Funct Genomics. 2013;12(3):254-78. PubMed PMID: 23709461. doi: 10.1093/bfgp/elt016

33. Consortium EP. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57-74. PubMed PMID: 22955616. Pubmed Central PMCID: 3439153. doi: 10.1038/nature11247

34. Li C, Lenhard B, Luscombe NM. Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome. Genome Res. 2018;28(5):676-88. PubMed PMID: 29618487. Pubmed Central PMCID: 5932608. doi: 10.1101/gr.231449.117

35. Uszczynska-Ratajczak B, Lagarde J, Frankish A, Guigo R, Johnson R. Towards a complete map of the human long non-coding RNA transcriptome. Nat Rev Genet. 2018. PubMed PMID: 29795125. doi: 10.1038/s41576-018-0017-y

36. Moran VA, Perera RJ, Khalil AM. Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs. Nucleic Acids Res. 2012;40(14):6391-400. PubMed PMID: 22492512. Pubmed Central PMCID: 3413108. doi: 10.1093/nar/gks296

37. Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154(1):26-46. PubMed PMID: 23827673. Pubmed Central PMCID: 3924787. doi: 10.1016/j.cell.2013.06.020

38. Wapinski O, Chang HY. Long noncoding RNAs and human disease. Trends Cell Biol. 2011;21(6):354-61. PubMed PMID: 21550244. doi: 10.1016/j.tcb.2011.04.001

39. Yang L, Froberg JE, Lee JT. Long noncoding RNAs: fresh perspectives into the RNA world. Trends Biochem Sci. 2014;39(1):35-43. PubMed PMID: 24290031. Pubmed Central PMCID: 3904784. doi: 10.1016/j.tibs.2013.10.002

40. Rinn JL. lncRNAs: linking RNA to chromatin. Cold Spring Harb Perspect Biol. 2014;6(8). PubMed PMID: 25085913. Pubmed Central PMCID: 4107985. doi: 10.1101/cshperspect.a018614

41. Bierhoff H, Schmitz K, Maass F, Ye J, Grummt I. Noncoding transcripts in sense and antisense orientation regulate the epigenetic state of ribosomal RNA genes. Cold Spring Harb Symp Quant Biol. 2010;75:357-64. PubMed PMID: 21502405. doi: 10.1101/sqb.2010.75.060

42. Faghihi MA, Wahlestedt C. Regulatory roles of natural antisense transcripts. Nat Rev Mol Cell Biol. 2009;10(9):637-43. PubMed PMID: 19638999. Pubmed Central PMCID: 2850559. doi: 10.1038/nrm2738

43. He Y, Vogelstein B, Velculescu VE, Papadopoulos N, Kinzler KW. The antisense transcriptomes of human cells. Science. 2008;322(5909):1855-7. PubMed PMID: 19056939. Pubmed Central PMCID: 2824178. 10.1126/science.1163853

44. Adachi N, Lieber MR. Bidirectional gene organization: a common architectural feature of the human genome. Cell. 2002;109(7):807-9. PubMed PMID: 12110178.

45. Uesaka M, Nishimura O, Go Y, Nakashima K, Agata K, Imamura T. Bidirectional promoters are the major source of gene activation-associated non-coding RNAs in mammals. BMC Genomics. 2014;15:35. PubMed PMID: 24438357. Pubmed Central PMCID: 3898825. doi: 10.1186/1471-2164-15-35

46. Wakano C, Byun JS, Di LJ, Gardner K. The dual lives of bidirectional promoters. Biochim Biophys Acta. 2012;1819(7):688-93. PubMed PMID: 22366276. Pubmed Central PMCID: 3371153. doi: 10.1016/j.bbagrm.2012.02.006

47. Wei W, Pelechano V, Jarvelin AI, Steinmetz LM. Functional consequences of bidirectional promoters. Trends Genet. 2011;27(7):267-76. PubMed PMID: 21601935. Pubmed Central PMCID: 3123404. 10.1016/j.tig.2011.04.002

48. Darrow EM, Chadwick BP. Boosting transcription by transcription: enhancer-associated transcripts. Chromosome Res. 2013;21(6-7):713-24. PubMed PMID: 24178450. Pubmed Central PMCID: 3867273. doi: 10.1007/s10577-013-9384-6

49. De Santa F, Barozzi I, Mietton F, Ghisletti S, Polletti S, Tusi BK, Muller H, Ragoussis J, Wei CL, Natoli G. A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biol. 2010;8(5):e1000384. PubMed PMID: 20485488. Pubmed Central PMCID: 2867938. doi: 10.1371/journal.pbio.1000384

50. Lam MT, Li W, Rosenfeld MG, Glass CK. Enhancer RNAs and regulated transcriptional programs. Trends Biochem Sci. 2014;39(4):170-82. PubMed PMID: 24674738. Pubmed Central PMCID: 4266492. doi: 10.1016/j.tibs.2014.02.007

51. 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(7295):182-7. PubMed PMID: 20393465. Pubmed Central PMCID: 3020079. doi: 10.1038/nature09033

52. Koch F, Fenouil R, Gut M, Cauchy P, Albert TK, Zacarias-Cabeza J, Spicuglia S, de la Chapelle AL, Heidemann M, Hintermair C, Eick D, Gut I, Ferrier P, Andrau JC. Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters. Nat Struct Mol Biol. 2011;18(8):956-63. PubMed PMID: 21765417. doi: 10.1038/nsmb.2085

53. 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(7455):511-5. PubMed PMID: 23728303. Pubmed Central PMCID: 3839578. doi: 10.1038/nature12209

54. 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(7455):516-20. PubMed PMID: 23728302. Pubmed Central PMCID: 3718886. doi: 10.1038/nature12210

55. Melo CA, Drost J, Wijchers PJ, van de Werken H, de Wit E, Oude Vrielink JA, Elkon R, Melo SA, Leveille N, Kalluri R, de Laat W, Agami R. eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol Cell. 2013;49(3):524-35. PubMed PMID: 23273978. doi: 10.1016/j.molcel.2012.11.021

56. 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(5):606-17. PubMed PMID: 23993744. Pubmed Central PMCID: 3786356. doi: 10.1016/j.molcel.2013.07.022

57. Hacisuleyman E, Goff LA, Trapnell C, Williams A, Henao-Mejia J, Sun L, McClanahan P, Hendrickson DG, Sauvageau M, Kelley DR, Morse M, Engreitz J, Lander ES, Guttman M, Lodish HF, Flavell R, Raj A, Rinn JL. Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre. Nat Struct Mol Biol. 2014;21(2):198-206. PubMed PMID: 24463464. Pubmed Central PMCID: 3950333. doi: 10.1038/nsmb.2764

58. 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(7341):120-4. PubMed PMID: 21423168. Pubmed Central PMCID: 3670758. doi: 10.1038/nature09819

59. 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(6):756-69. PubMed PMID: 18347095. Pubmed Central PMCID: 2275429. doi: 10.1101/gad.455708

60. Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, Finch CE, St Laurent G, 3rd, Kenny PJ, Wahlestedt C. Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretase. Nat Med. 2008;14(7):723-30. PubMed PMID: 18587408. Pubmed Central PMCID: 2826895. doi: 10.1038/nm1784

61. Mercer TR, Wilhelm D, Dinger ME, Solda G, Korbie DJ, Glazov EA, Truong V, Schwenke M, Simons C, Matthaei KI, Saint R, Koopman P, Mattick JS. Expression of distinct RNAs from 3' untranslated regions. Nucleic Acids Res. 2011;39(6):2393-403. PubMed PMID: 21075793. Pubmed Central PMCID: 3064787. doi: 10.1093/nar/gkq1158

62. Fitzgerald KA, Caffrey DR. Long noncoding RNAs in innate and adaptive immunity. Curr Opin Immunol. 2014;26:140-6. PubMed PMID: 24556411. Pubmed Central PMCID: 3932021. doi: 10.1016/j.coi.2013.12.001

63. Heward JA, Lindsay MA. Long non-coding RNAs in the regulation of the immune response. Trends Immunol. 2014;35(9):408-19. PubMed PMID: 25113636. doi: 10.1016/j.it.2014.07.005

64. Imamura K, Akimitsu N. Long Non-Coding RNAs Involved in Immune Responses. Front Immunol. 2014;5:573. PubMed PMID: 25431574. Pubmed Central PMCID: 4230175. doi: 10.3389/fimmu.2014.00573

65. Marques-Rocha JL, Samblas M, Milagro FI, Bressan J, Martinez JA, Marti A. Noncoding RNAs, cytokines, and inflammation-related diseases. FASEB J. 2015;29(9):3595-611. PubMed PMID: 26065857. doi: 10.1096/fj.14-260323

66. Satpathy AT, Chang HY. Long noncoding RNA in hematopoiesis and immunity. Immunity. 2015;42(5):792-804. PubMed PMID: 25992856. doi: 10.1016/j.immuni.2015.05.004

67. Sigdel KR, Cheng A, Wang Y, Duan L, Zhang Y. The Emerging Functions of Long Noncoding RNA in Immune Cells: Autoimmune Diseases. J Immunol Res. 2015;2015:848790. PubMed PMID: 26090502. Pubmed Central PMCID: 4451983. doi: 10.1155/2015/848790

68. Stachurska A, Zorro MM, van der Sijde MR, Withoff S. Small and Long Regulatory RNAs in the Immune System and Immune Diseases. Front Immunol. 2014;5:513. PubMed PMID: 25368617. Pubmed Central PMCID: 4202709. doi: 10.3389/fimmu.2014.00513

69. Valadkhan S, Gunawardane LS. lncRNA-mediated regulation of the interferon response. Virus Res. 2016;212:127-36. PubMed PMID: 26474526. Pubmed Central PMCID: 4744491. doi: 10.1016/j.virusres.2015.09.023

70. Yu AD, Wang Z, Morris KV. Long noncoding RNAs: a potent source of regulation in immunity and disease. Immunol Cell Biol. 2015;93(3):277-83. PubMed PMID: 25776990. doi: 10.1038/icb.2015.2

71. Atianand MK, Caffrey DR, Fitzgerald KA. Immunobiology of Long Noncoding RNAs. Annu Rev Immunol. 2017;35:177-98. PubMed PMID: 28125358. doi: 10.1146/annurev-immunol-041015-055459

72. Carpenter S. Long noncoding RNA: Novel links between gene expression and innate immunity. Virus Res. 2016;212:137-45. PubMed PMID: 26362525. doi: 10.1016/j.virusres.2015.08.019

73. Jiang M, Zhang S, Yang Z, Lin H, Zhu J, Liu L, Wang W, Liu S, Liu W, Ma Y, Zhang L, Cao X. Self-Recognition of an Inducible Host lncRNA by RIG-I Feedback Restricts Innate Immune Response. Cell. 2018;173(4):906-19 e13. PubMed PMID: 29706547. doi: 10.1016/j.cell.2018.03.064

74. Kambara H, Niazi F, Kostadinova L, Moonka DK, Siegel CT, Post AB, Carnero E, Barriocanal M, Fortes P, Anthony DD, Valadkhan S. Negative regulation of the interferon response by an interferon-induced long non-coding RNA. Nucleic Acids Res. 2014;42(16):10668-80. PubMed PMID: 25122750. Pubmed Central PMCID: 4176326. doi: 10.1093/nar/gku713

75. Xie Q, Chen S, Tian R, Huang X, Deng R, Xue B, Qin Y, Xu Y, Wang J, Guo M, Chen J, Tang S, Li G, Zhu H. LncITPRIP-1 Positively Regulates Innate Immune Response through Promoting Oligomerization and Activation of MDA5. J Virol. 2018. PubMed PMID: 29899107. doi: 10.1128/JVI.00507-18

76. Ma H, Han P, Ye W, Chen H, Zheng X, Cheng L, Zhang L, Yu L, Wu X, Xu Z, Lei Y, Zhang F. The Long Noncoding RNA NEAT1 Exerts Antihantaviral Effects by Acting as Positive Feedback for RIG-I Signaling. J Virol. 2017;91(9). PubMed PMID: 28202761. Pubmed Central PMCID: 5391460. doi: 10.1128/JVI.02250-16

77. Penkala I, Wang J, Syrett CM, Goetzl L, Lopez CB, Anguera MC. lncRHOXF1, a Long Noncoding RNA from the X Chromosome That Suppresses Viral Response Genes during Development of the Early Human Placenta. Mol Cell Biol. 2016;36(12):1764-75. PubMed PMID: 27066803. Pubmed Central PMCID: 4907097. doi: 10.1128/MCB.01098-15

78. Collier SP, Collins PL, Williams CL, Boothby MR, Aune TM. Cutting edge: influence of Tmevpg1, a long intergenic noncoding RNA, on the expression of Ifng by Th1 cells. J Immunol. 2012;189(5):2084-8. PubMed PMID: 22851706. Pubmed Central PMCID: 3424368. doi: 10.4049/jimmunol.1200774

79. Collier SP, Henderson MA, Tossberg JT, Aune TM. Regulation of the Th1 genomic locus from Ifng through Tmevpg1 by T-bet. J Immunol. 2014;193(8):3959-65. PubMed PMID: 25225667. Pubmed Central PMCID: 4185266. doi: 10.4049/jimmunol.1401099

80. Gomez JA, Wapinski OL, Yang YW, Bureau JF, Gopinath S, Monack DM, Chang HY, Brahic M, Kirkegaard K. The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-gamma locus. Cell. 2013;152(4):743-54. PubMed PMID: 23415224. Pubmed Central PMCID: 3577098. doi: 10.1016/j.cell.2013.01.015

81. Vigneau S, Rohrlich PS, Brahic M, Bureau JF. Tmevpg1, a candidate gene for the control of Theiler’s virus persistence, could be implicated in the regulation of gamma interferon. J Virol. 2003;77(10):5632-8. PubMed PMID: 12719555. Pubmed Central PMCID: 154023.

82. Bolen CR, Ding S, Robek MD, Kleinstein SH. Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression. Hepatology. 2014;59(4):1262-72. PubMed PMID: 23929627. Pubmed Central PMCID: 3938553. doi: 10.1002/hep.26657

83. Hertzog P, Forster S, Samarajiwa S. Systems biology of interferon responses. J Interferon Cytokine Res. 2011;31(1):5-11. PubMed PMID: 21226606. doi: 10.1089/jir.2010.0126

84. Hu X, Ivashkiv LB. Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity. 2009;31(4):539-50. PubMed PMID: 19833085. Pubmed Central PMCID: 2774226. doi: 10.1016/j.immuni.2009.09.002

85. Pollard KM, Cauvi DM, Toomey CB, Morris KV, Kono DH. Interferon-gamma and systemic autoimmunity. Discov Med. 2013;16(87):123-31. PubMed PMID: 23998448. Pubmed Central PMCID: 3934799.

86. Rusinova I, Forster S, Yu S, Kannan A, Masse M, Cumming H, Chapman R, Hertzog PJ. Interferome v2.0: an updated database of annotated interferon-regulated genes. Nucleic Acids Res. 2013;41(Database issue):D1040-6. PubMed PMID: 23203888. Pubmed Central PMCID: 3531205. doi: 10.1093/nar/gks1215

87. Zhou Z, Hamming OJ, Ank N, Paludan SR, Nielsen AL, Hartmann R. Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases. J Virol. 2007;81(14):7749-58. PubMed PMID: 17507495. Pubmed Central PMCID: 1933366. doi: 10.1128/JVI.02438-06

88. Meyer O. Interferons and autoimmune disorders. Joint Bone Spine. 2009;76(5):464-73. PubMed PMID: 19773191. doi: 10.1016/j.jbspin.2009.03.012

89. Ding H, Liu J, Liu B, Zeng Y, Chen P, Su Y. Long noncoding RNA PVT1 inhibits interferon-alpha mediated therapy for hepatocellular carcinoma cells by interacting with signal transducer and activator of transcription 1. Biochem Biophys Res Commun. 2018;500(4):973-80. PubMed PMID: 29715456. doi: 10.1016/j.bbrc.2018.04.219

90. Ho HH, Ivashkiv LB. Role of STAT3 in type I interferon responses. Negative regulation of STAT1-dependent inflammatory gene activation. J Biol Chem. 2006;281(20):14111-8. PubMed PMID: 16571725. doi: 10.1074/jbc.M511797200

91. Mahony R, Gargan S, Roberts KL, Bourke N, Keating SE, Bowie AG, O’Farrelly C, Stevenson NJ. A novel anti-viral role for STAT3 in IFN-alpha signalling responses. Cell Mol Life Sci. 2017;74(9):1755-64. PubMed PMID: 27988795. doi: 10.1007/s00018-016-2435-3

92. Wang WB, Levy DE, Lee CK. STAT3 negatively regulates type I IFN-mediated antiviral response. J Immunol. 2011;187(5):2578-85. PubMed PMID: 21810606. doi: 10.4049/jimmunol.1004128

93. Xiong Y, Yuan J, Zhang C, Zhu Y, Kuang X, Lan L, Wang X. The STAT3-regulated long non-coding RNA Lethe promote the HCV replication. Biomed Pharmacother. 2015;72:165-71. PubMed PMID: 26054691. doi: 10.1016/j.biopha.2015.04.019

94. Tang WG, Hu B, Sun HX, Sun QM, Sun C, Fu PY, Yang ZF, Zhang X, Zhou CH, Fan J, Ren N, Xu Y. Long non-coding RNA00364 represses hepatocellular carcinoma cell proliferation via modulating p-STAT3-IFIT2 signaling axis. Oncotarget. 2017;8(60):102006-19. PubMed PMID: 29254221. Pubmed Central PMCID: 5731931. doi: 10.18632/oncotarget.22039

95. Porritt RA, Hertzog PJ. Dynamic control of type I IFN signalling by an integrated network of negative regulators. Trends Immunol. 2015;36(3):150-60. PubMed PMID: 25725583. doi: 10.1016/j.it.2015.02.002

96. Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol. 2007;7(6):454-65. PubMed PMID: 17525754. doi: 10.1038/nri2093

97. Green DS, Young HA, Valencia JC. Current prospects of type II interferon gamma signaling and autoimmunity. J Biol Chem. 2017;292(34):13925-33. PubMed PMID: 28652404. Pubmed Central PMCID: 5572907. doi: 10.1074/jbc.R116.774745

98. Dijkstra JM, Alexander DB. The “NF-k B interacting long noncoding RNA” (NKILA) transcript is antisense to cancer-associated gene PMEPA1. F1000Res. 2015;4:96. PubMed PMID: 26069731. Pubmed Central PMCID: 4431381. doi: 10.12688/f1000research.6400.1

99. Imam H, Bano AS, Patel P, Holla P, Jameel S. The lncRNA NRON modulates HIV-1 replication in a NFAT-dependent manner and is differentially regulated by early and late viral proteins. Sci Rep. 2015;5:8639. PubMed PMID: 25728138. Pubmed Central PMCID: 4345339. doi: 10.1038/srep08639

100. Pan JX. LncRNA H19 promotes atherosclerosis by regulating MAPK and NF-kB signaling pathway. Eur Rev Med Pharmacol Sci. 2017;21(2):322-8. PubMed PMID: 28165553.

101. Wang H, Li L, Yin L. Silencing LncRNA LOXL1-AS1 attenuates mesenchymal characteristics of glioblastoma via NF-kappaB pathway. Biochem Biophys Res Commun. 2018;500(2):518-24. PubMed PMID: 29678575. doi: 10.1016/j.bbrc.2018.04.133

102. Zang Y, Zhou X, Wang Q, Li X, Huang H. LncRNA FIRRE/NF-kB feedback loop contributes to OGD/R injury of cerebral microglial cells. Biochem Biophys Res Commun. 2018;501(1):131-8. PubMed PMID: 29715458. doi: 10.1016/j.bbrc.2018.04.194

103. Wang HK, Yan H, Wang K, Wang J. Dynamic regulation effect of long non-coding RNA-UCA1 on NF-kB in hippocampus of epilepsy rats. Eur Rev Med Pharmacol Sci. 2017;21(13):3113-9. PubMed PMID: 28742194.

104. Josset L, Tchitchek N, Gralinski LE, Ferris MT, Eisfeld AJ, Green RR, Thomas MJ, Tisoncik-Go J, Schroth GP, Kawaoka Y, Manuel de Villena FP, Baric RS, Heise MT, Peng X, Katze MG. Annotation of long non-coding RNAs expressed in collaborative cross founder mice in response to respiratory virus infection reveals a new class of interferon-stimulated transcripts. RNA Biol. 2014;11(7):875-90. PubMed PMID: 24922324. Pubmed Central PMCID: 4179962. doi: 10.4161/rna.29442

105. Peng X, Gralinski L, Armour CD, Ferris MT, Thomas MJ, Proll S, Bradel-Tretheway BG, Korth MJ, Castle JC, Biery MC, Bouzek HK, Haynor DR, Frieman MB, Heise M, Raymond CK, Baric RS, Katze MG. Unique signatures of long noncoding RNA expression in response to virus infection and altered innate immune signaling. MBio. 2010;1(5). PubMed PMID: 20978541. Pubmed Central PMCID: 2962437. doi: 10.1128/mBio.00206-10

106. Kambara H, Gunawardane L, Zebrowski E, Kostadinova L, Jobava R, Krokowski D, Hatzoglou M, Anthony DD, Valadkhan S. Regulation of Interferon-Stimulated Gene BST2 by a lncRNA Transcribed from a Shared Bidirectional Promoter. Front Immunol. 2014;5:676. PubMed PMID: 25688240. Pubmed Central PMCID: 4311693. doi: 10.3389/fimmu.2014.00676

107. Barriocanal M, Carnero E, Segura V, Fortes P. Long Non-Coding RNA BST2/BISPR is Induced by IFN and Regulates the Expression of the Antiviral Factor Tetherin. Front Immunol. 2014;5:655. PubMed PMID: 25620967. Pubmed Central PMCID: 4288319. doi: 10.3389/fimmu.2014.00655

108. Carnero E, Barriocanal M, Segura V, Guruceaga E, Prior C, Borner K, Grimm D, Fortes P. Type I Interferon Regulates the Expression of Long Non-Coding RNAs. Front Immunol. 2014;5:548. PubMed PMID: 25414701. Pubmed Central PMCID: 4222131. doi: 10.3389/fimmu.2014.00548

109. Ouyang J, Zhu X, Chen Y, Wei H, Chen Q, Chi X, Qi B, Zhang L, Zhao Y, Gao GF, Wang G, Chen JL. NRAV, a long noncoding RNA, modulates antiviral responses through suppression of interferon-stimulated gene transcription. Cell Host Microbe. 2014;16(5):616-26. PubMed PMID: 25525793. doi: 10.1016/j.chom.2014.10.001

110. Wagner LA, Christensen CJ, Dunn DM, Spangrude GJ, Georgelas A, Kelley L, Esplin MS, Weiss RB, Gleich GJ. EGO, a novel, noncoding RNA gene, regulates eosinophil granule protein transcript expression. Blood. 2007;109(12):5191-8. PubMed PMID: 17351112. Pubmed Central PMCID: 1890841. doi: 10.1182/blood-2006-06-027987

111. Carnero E, Barriocanal M, Prior C, Pablo Unfried J, Segura V, Guruceaga E, Enguita M, Smerdou C, Gastaminza P, Fortes P. Long noncoding RNA EGOT negatively affects the antiviral response and favors HCV replication. EMBO Rep. 2016;17(7):1013-28. PubMed PMID: 27283940. Pubmed Central PMCID: 4931568. doi: 10.15252/embr.201541763

112. Nishitsuji H, Ujino S, Yoshio S, Sugiyama M, Mizokami M, Kanto T, Shimotohno K. Long noncoding RNA #32 contributes to antiviral responses by controlling interferon-stimulated gene expression. Proc Natl Acad Sci U S A. 2016;113(37):10388-93. PubMed PMID: 27582466. Pubmed Central PMCID: 5027408. doi: 10.1073/pnas.1525022113