Identifying Interactions Between Long Noncoding RNAs and Diseases Based on Computational Methods

  • Wei Lan
  • Liyu Huang
  • Dehuan Lai
  • Qingfeng ChenEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1754)


With the development and improvement of next-generation sequencing technology, a great number of noncoding RNAs have been discovered. Long noncoding RNAs (lncRNAs) are the biggest kind of noncoding RNAs with more than 200 nt nucleotides in length. There are increasing evidences showing that lncRNAs play key roles in many biological processes. Therefore, the mutation and dysregulation of lncRNAs have close association with a number of complex human diseases. Identifying the most likely interaction between lncRNAs and diseases becomes a fundamental challenge in human health. A common view is that lncRNAs with similar function tend to be related to phenotypic similar diseases. In this chapter, we firstly introduce the concept of lncRNA, their biological features, and available data resources. Further, the recent computational approaches are explored to identify interactions between long noncoding RNAs and diseases, including their advantages and disadvantages. The key issues and potential future works of predicting interactions between long noncoding RNAs and diseases are also discussed.

Key words

Long noncoding RNA Human disease Biological networks Heterogeneous data fusion Machine learning 



This work is supported in part by the National Natural Science Foundation of China under Grant No. 61702122, 61751314 and 61363025; a key project of Natural Science Foundation of Guangxi 2017GXNSFDA198033 and a key research and development plan of Guangxi AB17195055; the Director Open Fund of Qinzhou City Key Laboratory of Advanced Technology of Internet of Things IOT2017A04.


  1. 1.
    Altshuler DL, Durbin RM, Abecasis GR, Bentley DR, Chakravarti A, Clark AG, Collins FS, Vega FMDL, Donnelly P, Egholm M (2010) Consortium, T.G.P.: a map of human genome variation from population-scale sequencing. Nature 467(7319):1061–1073PubMedCrossRefGoogle Scholar
  2. 2.
    Chen Q, Luo H, Zhang C, Chen P (2015) Bioinformatics in protein kinases regulatory network and drug discovery. Math Biosci 262:147–156PubMedCrossRefGoogle Scholar
  3. 3.
    Green ED, Guyer MS (2011) Charting a course for genomic medicine from base pairs to bedside. Nature 470(7333):204PubMedCrossRefGoogle Scholar
  4. 4.
    Yan C, Wang J, Lan W, Wu F, Pan Y (2017) SDTRLS: Predicting Drug-Target Interactions for Complex Diseases Based on Chemical Substructures. Complexity 2017 (2017), Article ID 2713280Google Scholar
  5. 5.
    Chen Q, Chen P, Zhang C (2016) Effective classification of conserved RNA secondary structures using interval based similarity. IEEE Intell Syst 31(3):78–85CrossRefGoogle Scholar
  6. 6.
    Chen Q, Lan W, Wang J (2013) Mining Featured Patterns of MiRNA Interaction based on Sequence and Structure Similarity. IEEE Trans Comput Biol Bioinformatics 10(2):415–422CrossRefGoogle Scholar
  7. 7.
    Guttman M, Amit I, Garber M, French C, Lin M, Feldser D, Huarte M, Zuk O, Carey B, Cassady J, Cabili M, Jaenisch R, Mikkelsen T, Jacks T, Hacohen N, Bernstein B, Kellis M, Regev A, Rinn J, Lander E (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458(7235):223–227PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Louro R, Smirnova AS, Verjovski-Almeida S (2009) Long intronic noncoding RNA transcription: expression noise or expression choice. Genomics 93(4):291–298PubMedCrossRefGoogle Scholar
  9. 9.
    Lan W, Chen Q, Li T, Yuan C, Mann S, Chen B (2014) Identification of important positions within miRNAs by integrating sequential and structural features. Curr Protein Pept Sci 15(6):591–597PubMedCrossRefGoogle Scholar
  10. 10.
    Guttman M, Rinn JL (2012) Modular regulatory principles of large non-coding RNAs. Nature 482(7385):339–346PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Mercer T, Dinger M, Mattick J (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10(3):155–159PubMedCrossRefGoogle Scholar
  12. 12.
    Chen Q, Li G, Chen YP (2011) Interval-based distance function for identifying RNA structure candidates. J Theor Biol 269(1):280–286PubMedCrossRefGoogle Scholar
  13. 13.
    Yang L, Lin C, Jin C, Yang JC, Tanasa B, Li W, Merkurjev D, Ohgi KA, Meng D, Zhang J (2013) LncRNA-dependent mechanisms of androgen receptor-regulated gene activation programs. Nature 500(7464):598–602PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Li H, Yu B, Li J, Su L, Yan M, Zhu Z, Liu B (2014) Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer. Oncotarget 5(8):2318–2329PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Laurent GS, Wahlestedt C, Kapranov P (2015) The Landscape of long noncoding RNA classification. Trends Genet 31(5):239CrossRefGoogle Scholar
  16. 16.
    Reddy TB, Thomas AD, Stamatis D, Bertsch J, Isbandi M, Jansson J, Mallajosyula J, Pagani I, Lobos EA, Kyrpides NC (2014) The Genomes OnLine Database (GOLD) v.5: a metadata management system based on a four level (meta)genome project classification. Nucleic Acids Res 43(Database issue):D1099PubMedPubMedCentralGoogle Scholar
  17. 17.
    Bond CS, Fox AH (2009) Paraspeckles: nuclear bodies built on long noncoding RNA. J Cell Biol 186(5):637PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Geisler S, Coller J (2013) RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat Rev Mol Cell Biol 14(11):699–712PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Ponting C, Oliver P, Reik W (2009) Evolution and functions of long noncoding RNAs. Cell 136(4):629–641PubMedCrossRefGoogle Scholar
  20. 20.
    Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem 81(1):145PubMedCrossRefGoogle Scholar
  21. 21.
    Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY (2010) Long noncoding RNA as modular scaffold of histone modification complexes. Science 329(5992):689PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Batista P, Chang H (2013) Long noncoding RNAs: cellular address codes in development and disease. Cell 152(6):1298PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Gutschner T, Hämmerle M, Eissmann M, Hsu J, Kim Y, Hung G, Revenko A, Arun G, Stentrup M, Gross M, Zörnig M, MacLeod A, Spector D, Diederichs S (2013) The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res 73(3):1180–1189PubMedCrossRefGoogle Scholar
  24. 24.
    Bhartiya D, Kapoor S, Jalali S, Sati S, Kaushik K, Sachidanandan C, Sivasubbu S, Scaria V (2012) Conceptual approaches for lncRNA drug discovery and future strategies. Expert Opin Drug Discovery 7(6):503–513CrossRefGoogle Scholar
  25. 25.
    Yang G, Lu X, Yuan L (2014) LncRNA: a link between RNA and cancer. Biochim Biophys Acta 1839(11):1097PubMedCrossRefGoogle Scholar
  26. 26.
    Xing C, Yan CC, Xu Z, You ZH (2017) Long non-coding RNAs and complex diseases: from experimental results to computational models. Brief Bioinform 18:558Google Scholar
  27. 27.
    Schriml LM, Arze C, Nadendla S, Chang YW, Mazaitis M, Felix V, Feng G, Kibbe WA (2012) Disease ontology: a backbone for disease semantic integration. Nucleic Acids Res 40(Database issue):940–946CrossRefGoogle Scholar
  28. 28.
    Amberger JS, Bocchini CA, Schiettecatte F, Scott AF, Hamosh A (2014) online mendelian inheritance in man (OMIM), an online catalog of human genes and genetic disorders. Nucleic Acids Res 43(Database issue):D789PubMedPubMedCentralGoogle Scholar
  29. 29.
    Becker KG, Barnes KC, Bright TJ, Wang SA (2004) The genetic association database. Nat Genet 36(5):431–432PubMedCrossRefGoogle Scholar
  30. 30.
    Piñero J, Queraltrosinach N, Bravo À, Deupons J, Bauermehren A, Baron M, Sanz F, Furlong LI (2015) DisGeNET: a discovery platform for the dynamical exploration of human diseases and their genes. Database 2015(3):bav028PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Volders PJ, Helsens K, Wang X, Menten B, Martens L, Gevaert K, Vandesompele J, Mestdagh P (2013) LNCipedia: a database for annotated human lncRNA transcript sequences and structures. Nucleic Acids Res 41(Database issue):246–251CrossRefGoogle Scholar
  32. 32.
    Zhao Y, Li H, Fang S, Kang Y, Wu W, Hao Y, Li Z, Bu D, Sun N, Zhang MQ (2016) NONCODE 2016: an informative and valuable data source of long non-coding RNAs. Nucleic Acids Res 44(Database issue):D203–D208PubMedCrossRefGoogle Scholar
  33. 33.
    Chakraborty S, Deb A, Maji RK, Saha S, Ghosh Z (2013) LncRBase: an enriched resource for lncRNA information. PLoS One 9(9):e108010CrossRefGoogle Scholar
  34. 34.
    Ma L, Li A, Zou D, Xu X, Xia L, Yu J, Bajic VB, Zhang Z (2015) LncRNAWiki: harnessing community knowledge in collaborative curation of human long non-coding RNAs. Nucleic Acids Res 43(Database issue):187–192CrossRefGoogle Scholar
  35. 35.
    Quek XC, Thomson DW, Maag JL, Bartonicek N, Signal B, Clark MB, Gloss BS, Dinger ME (2015) lncRNAdb v2.0: expanding the reference database for functional long noncoding RNAs. Nucleic Acids Res 43(Database issue):168–173CrossRefGoogle Scholar
  36. 36.
    Chen G, Wang Z, Wang D, Qiu C, Liu M, Chen X, Zhang Q, Yan G, Cui Q (2013) LncRNADisease: a database for long-non-coding RNA-associated diseases. Nucleic Acids Res 41(Database issue):D983PubMedGoogle Scholar
  37. 37.
    Ning S, Zhang J, Wang P, Zhi H, Wang J, Liu Y, Gao Y, Guo M, Yue M, Wang L (2016) Lnc2Cancer: a manually curated database of experimentally supported lncRNAs associated with various human cancers. Nucleic Acids Res 44(D1):D980PubMedCrossRefGoogle Scholar
  38. 38.
    Wang Y, Chen L, Chen B, Li X, Kang J, Fan K, Hu Y, Xu J, Yi L, Yang J (2013) Mammalian ncRNA-disease repository: a global view of ncRNA-mediated disease network. Cell Death Dis 4(8):e765PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Lan W, Wang J, Li M, Peng W, Wu F (2015) Computational approaches for prioritizing candidate disease genes based on PPI networks. Tsinghua Sci Technol 20(5):500–512CrossRefGoogle Scholar
  40. 40.
    Guo X, Gao L, Wang Y, Chiu DK, Wang T, Deng Y (2015) Advances in long noncoding RNAs: identification, structure prediction and function annotation. Brief Funct Genomics 15(1):38PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Chen LL, Carmichael GG (2010) Decoding the function of nuclear long noncoding RNAs. Curr Opin Cell Biol 22(3):357–364PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Peng W, Lan W, Zhong J, Wang J, Pan Y (2017) A novel method of predicting microRNA-disease associations based on microRNA, disease, gene and environment factor networks. Methods 124:69. Scholar
  43. 43.
    Yan C, Wang J, Ni P, Lan W, Wu F, Pan Y (2017) DNRLMF-MDA: Predicting microRNA-disease associations based on similarities of microRNAs and diseases. IEEE Transa Comput Biol Bioinformatics 99:1–1Google Scholar
  44. 44.
    Sun J, Shi H, Wang Z, Zhang C, Liu L, Wang L, He W, Hao D, Liu S, Zhou M (2014) Inferring novel lncRNA-disease associations based on a random walk model of a lncRNA functional similarity network. Mol Biosyst 10(8):2074–2081PubMedCrossRefGoogle Scholar
  45. 45.
    Cheng L, Shi H, Wang Z, Hu Y, Yang H, Zhou C, Sun J, Zhou M (2016) IntNetLncSim: an integrative network analysis method to infer human lncRNA functional similarity. Oncotarget 7(30):47864–47874PubMedPubMedCentralGoogle Scholar
  46. 46.
    Chen X, You ZH, Yan GY, Gong DW (2016) IRWRLDA: improved random walk with restart for lncRNA-disease association prediction. Oncotarget 7(36):57919PubMedPubMedCentralGoogle Scholar
  47. 47.
    Zhou M, Wang X, Li J, Hao D, Wang Z, Shi H, Han L, Zhou H, Sun J (2015) Prioritizing candidate disease-related long non-coding RNAs by walking on the heterogeneous lncRNA and disease network. Mol Biosyst 11(3):760–769PubMedCrossRefGoogle Scholar
  48. 48.
    Alaimo S, Giugno R, Pulvirenti A (2014) ncPred: ncRNA-disease association prediction through tripartite network-based inference. Front Bioeng Biotechnol 2:71PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Liu Y, Zhang R, Qiu F, Li K, Zhou Y, Shang D, Xu Y (2015) Construction of a lncRNA-PCG bipartite network and identification of cancer-related lncRNAs: a case study in prostate cancer. Mol Biosyst 11(2):384PubMedCrossRefGoogle Scholar
  50. 50.
    Yao Q, Wu L, Li J, Yang LG, Sun Y, Li Z, He S, Feng F, Li H, Li Y (2017) Global prioritizing disease candidate lncRNAs via a multi-level composite network. Sci Rep 7:39516PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Ganegoda GU, Li M, Wang W, Feng Q (2015) Heterogeneous network model to infer human disease-long intergenic non coding RNA associations. IEEE Trans Nanobioscience 14(2):175–183PubMedCrossRefGoogle Scholar
  52. 52.
    Lan W, Wang J, Min L, Jin L, Wu FX, Pan Y (2016) Predicting microRNA-disease associations based on improved microRNA and disease similarities. IEEE Transa Comput Biol Bioinformatics 99:1–1Google Scholar
  53. 53.
    Lan W, Wang J, Li M, Liu J, Li Y, Wu FX, Pan Y (2016) Predicting drug-target interaction using positive-unlabeled learning. Neurocomputing 206(C):50–57CrossRefGoogle Scholar
  54. 54.
    Liu J, Li M, Lan W, Wu FX, Pan Y, Wang J (2016) Classification of Alzheimer’s disease using whole brain hierarchical network. IEEE Transa Comput Biol Bioinformatics 99:1–1Google Scholar
  55. 55.
    Peng W, Lan W, Zeng Y, Wang J, Yi P (2016) A Framework for integrating multiple biological networks to predict microRNA-disease associations. IEEE Trans Nanobiosci 99:1–1Google Scholar
  56. 56.
    Zhao T, Xu J, Liu L, Bai J, Xu C, Xiao Y, Li X, Zhang L (2015) Identification of cancer-related lncRNAs through integrating genome, regulome and transcriptome features. Mol Biosyst 11(1):126PubMedCrossRefGoogle Scholar
  57. 57.
    Lan W, Li M, Zhao K, Jin L, Wu FX, Yi P, Wang J (2017) LDAP: a web server for lncRNA-disease association prediction. Bioinformatics 33:458PubMedGoogle Scholar
  58. 58.
    Chen X, Yan GY (2013) Novel human lncRNA-disease association inference based on lncRNA expression profiles. Bioinformatics 29(20):2617PubMedCrossRefGoogle Scholar
  59. 59.
    Chen X, Yan CC, Luo C, Ji W, Zhang Y, Dai Q (2015) Constructing lncRNA functional similarity network based on lncRNA-disease associations and disease semantic similarity. Sci Rep 5:11338PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Huang YA, Chen X, You ZH, Huang DS, Chan KC (2016) ILNCSIM: improved lncRNA functional similarity calculation model. Oncotarget 7(18):25902–25914PubMedPubMedCentralGoogle Scholar
  61. 61.
    Chen X, Huang YA, Wang XS, You ZH, Chan KCC (2016) FMLNCSIM: fuzzy measure-based lncRNA functional similarity calculation model. Oncotarget 7(29):45948–45958PubMedPubMedCentralGoogle Scholar
  62. 62.
    Biswas AK, Kang M, Kim DC, Ding CHQ, Zhang B, Wu X, Gao JX (2015) Inferring disease associations of the long non-coding RNAs through non-negative matrix factorization. Network Modeling Analysis in Health Informatics and. Bioinformatics 4(1):1–17Google Scholar
  63. 63.
    Li M, Zheng R, Zhang H, Wang J, Pan Y (2014) Effective identification of essential proteins based on priori knowledge, network topology and gene expressions. Methods 67(3):325–333PubMedCrossRefGoogle Scholar
  64. 64.
    Li M, Zheng R, Li Q, Wang J, Wu FX, Zhang Z (2016) Prioritizing disease genes by using search engine algorithm. Curr Bioinformatics 11:195CrossRefGoogle Scholar
  65. 65.
    Liu MX, Chen X, Chen G, Cui QH, Yan GY (2014) A computational framework to infer human disease-associated long noncoding RNAs. PLoS One 9(1):e84408PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Chen X (2015) Predicting lncRNA-disease associations and constructing lncRNA functional similarity network based on the information of miRNA. Sci Rep 5:13186PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Ying L, Ye H, Han S, Liang Y (2017) Identification and functional inference for tumor-associated long non-coding RNA. IEEE Transa Comput Biol Bioinformatics 99:1–1Google Scholar
  68. 68.
    Cogill SB, Wang L (2014) Co-expression network analysis of human lncRNAs and cancer genes. Cancer Informatics 13(Suppl 5):49–59PubMedPubMedCentralGoogle Scholar
  69. 69.
    Zhou M, Zhong L, Xu W, Sun Y, Zhang Z, Zhao H, Yang L, Sun J (2016) Discovery of potential prognostic long non-coding RNA biomarkers for predicting the risk of tumor recurrence of breast cancer patients. Sci Rep 6:31038PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Peng W, Guo Q, Yue G, Hui Z, Yan Z, Yue L, Zhang J, Ming Y, Guo M, Ning S (2017) Improved method for prioritization of disease associated lncRNAs based on ceRNA theory and functional genomics data. Oncotarget 8(3):4642–4655CrossRefGoogle Scholar
  71. 71.
    Wery M, Descrimes M, Vogt N, Dallongeville AS, Gautheret D, Morillon A (2016) Nonsense-mediated decay restricts LncRNA levels in yeast unless blocked by double-stranded RNA structure. Mol Cell 61(3):379–392PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Chodroff RA, Goodstadt L, Sirey TM, Oliver PL, Davies KE, Green ED, Molnár Z, Ponting CP (2010) Long noncoding RNA genes: conservation of sequence and brain expression among diverse amniotes. Genome Biol 11(7):R72PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Mitra SA, Mitra AP, Triche TJ (2012) A central role for long non-coding RNA in cancer. Front Genet 3:17PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Sanbonmatsu KY (2015) Towards structural classification of long non-coding RNAs. Biochim Biophys Acta 1859(1):41–45PubMedCrossRefGoogle Scholar
  75. 75.
    Liu J, Wang J, Hu B, Wu FX, Pan Y (2017) Alzheimer’s disease classification based on individual hierarchical networks constructed with 3D texture features. IEEE Trans Nanobioscience 16:428. Scholar
  76. 76.
    Da SL, Baldassarre A, Masotti A (2012) Bioinformatics tools and novel challenges in long non-coding RNAs (lncRNAs) functional analysis. Int J Mol Sci 13(1):97–114Google Scholar
  77. 77.
    Grote P, Wittler L, Hendrix D, Koch F, Währisch S, Beisaw A, Macura K, Bläss G, Kellis M, Werber M (2013) The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev Cell 24(2):206PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Wei Lan
    • 1
  • Liyu Huang
    • 2
  • Dehuan Lai
    • 1
  • Qingfeng Chen
    • 1
    • 3
    Email author
  1. 1.School of Computer, Electronics and InformationGuangxi UniversityNanningChina
  2. 2.Information and Network CenterGuangxi UniversityNanningChina
  3. 3.State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresourcesGuangxi UniversityNanningChina

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