LncRNAs: A new trend in molecular biology of diseases; A review

Reza Gheitasi, Hamed Manoochehri, Neda Dalil, Alireza Gharib

DOI: 10.22122/cdj.v0i0.418


BACKGROUND: Non-coding ribonucleotide sequences, including short and long-term ribonucleic acid (RNA) molecules, are a major part of the gene expression products, which have recently been identified on a large genomic scale. The long non-coding RNAs (lncRNAs) have a length of greater than 200 nucleotides. Only a small fraction of the function of lncRNA molecules is known to date.

METHODS: PubMed, Scopus, Embase, and Google Scholar were searched from January 2000 to May 2018. Based on the study inclusion and exclusion criteria and specific keywords, 92 original, relevant, experimental studies with moderate bias were selected. LncRNAs were evaluated as a new trend in molecular biology of diseases.

RESULTS: Our analysis showed that the presently available evidence confirmed that lncRNAs can be a tool for the diagnosis and prognosis of many diseases and alternative therapies.

CONCLUSION: LncRNAs are an emerging field of investigation as they are suggested to regulate key biological processes, including cellular proliferation and differentiation, and their aberrant expression is associated with many diseases. An improved understanding of the role of lncRNAs in disease would provide valuable information about key biological-promoting pathways and might be highly useful for diagnostic, prognostic, and alternative therapies assessments. This knowledge might also lead to advancement in the management of disease through the development of novel, personalized lncRNAs-based therapies.


Long Non-Coding RNA; Autoimmune Disease; Neurodegenerative Diseases; Cardiovascular Diseases; Immune System Diseases

Full Text:



Cakir BO, Adamson P, Cingi C. Epidemiology and economic burden of nonmelanoma skin cancer. Facial Plast Surg Clin North Am 2012; 20(4): 419-22.

Leiter U, Garbe C. Epidemiology of melanoma and nonmelanoma skin cancer-the role of sunlight. In: Reichrath J, Editor. Sunlight, Vitamin D and Skin Cancer. Berlin, Germany: Springer Science &

Business Media; 2009. p. 89-103.

Cho AH, Lee MG, Lee JD. Radionuclide therapy for skin malignancies. In: Baum RP, Editor. Therapeutic nuclear medicine. Berlin, Germany: Springer; 2014. p. 717-24.

Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988; 319(9): 525-32.

Jerant AF, Johnson JT, Sheridan CD, Caffrey TJ. Early detection and treatment of skin cancer. Am Fam Physician 2000; 62(2): 357-6, 381.

Gibb EA, Vucic EA, Enfield KS, Stewart GL, Lonergan KM, Kennett JY, et al. Human cancer long non-coding RNA transcriptomes. PLoS One 2011; 6(10): e25915.

Mattick JS. Long noncoding RNAs in cell and developmental biology. Semin Cell Dev Biol 2011; 22(4): 327.

Batista PJ, Chang HY. Long noncoding RNAs: Cellular address codes in development and disease. Cell 2013; 152(6): 1298-307.

Spitale RC, Flynn RA, Zhang QC, Crisalli P, Lee B, Jung JW, et al. Structural imprints in vivo decode RNA regulatory mechanisms. Nature 2015; 519(7544): 486-90.

Maruyama R, Suzuki H. Long noncoding RNA involvement in cancer. BMB Rep 2012; 45(11): 604-11.

Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: Insights into functions. Nat Rev Genet 2009; 10(3): 155-9.

Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. Cancer Discov 2011; 1(5): 391-407.

Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007; 447(7146): 799-816.

Heward JA, Lindsay MA. Long non-coding RNAs in the regulation of the immune response. Trends Immunol 2014; 35(9): 408-19.

Esteller M. Non-coding RNAs in human disease. Nat Rev Genet 2011; 12(12): 861-74.

Okazaki Y, Furuno M, Kasukawa T, Adachi J, Bono H, Kondo S, et al. Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature 2002; 420(6915): 563-73.

Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell 2009; 136(4): 629-41.

Kapusta A, Kronenberg Z, Lynch VJ, Zhuo X, Ramsay L, Bourque G, et al. Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs. PLoS Genet 2013; 9(4): e1003470.

Feuerhahn S, Iglesias N, Panza A, Porro A, Lingner J. TERRA biogenesis, turnover and implications for function. FEBS Lett 2010; 584(17): 3812-8.

Church DM, Goodstadt L, Hillier LW, Zody MC, Goldstein S, She X, et al. Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol 2009; 7(5): e1000112.

Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, et al. The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression. Genome Res 2012; 22(9): 1775-89.

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(7): 1537-50.

Pauli A, Valen E, Lin MF, Garber M, Vastenhouw NL, Levin JZ, et al. Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. Genome Res 2012; 22(3): 577-91.

Ponjavic J, Ponting CP, Lunter G. Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs. Genome Res 2007; 17(5): 556-65.

Tilgner H, Knowles DG, Johnson R, Davis CA, Chakrabortty S, Djebali S, et al. 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(9): 1616-25.

Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 2013; 495(7441): 333-8.

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(21): 2392-407.

Yin QF, Yang L, Zhang Y, Xiang JF, Wu YW, Carmichael GG, et al. Long noncoding RNAs with snoRNA ends. Mol Cell 2012; 48(2): 219-30.

Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 2010; 142(3): 409-19.

Da Sacco L, Baldassarre A, Masotti A. Bioinformatics tools and novel challenges in long non-coding RNAs (lncRNAs) functional analysis. Int J Mol Sci 2012; 13(1): 97-114.

Paralkar VR, Weiss MJ. Long noncoding RNAs in biology and hematopoiesis. Blood 2013; 121(24): 4842-6.

Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev 2011; 25(18): 1915-27.

Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, et al. The transcriptional landscape of the mammalian genome. Science 2005; 309(5740): 1559-63.

Shi X, Sun M, Liu H, Yao Y, Song Y. Long non-coding RNAs: A new frontier in the study of human diseases. Cancer Lett 2013; 339(2): 159-66.

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(107): ra8.

Kudla G, Lipinski L, Caffin F, Helwak A, Zylicz M. High guanine and cytosine content increases mRNA levels in mammalian cells. PLoS Biol 2006; 4(6): e180.

Zuker M. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 2003; 31(13): 3406-15.

Sukosd Z, Knudsen B, Kjems J, Pedersen CN. PPfold 3.0: Fast RNA secondary structure prediction using phylogeny and auxiliary data. Bioinformatics 2012; 28(20): 2691-2.

Puton T, Kozlowski LP, Rother KM, Bujnicki JM. CompaRNA: A server for continuous benchmarking of automated methods for RNA secondary structure prediction. Nucleic Acids Res 2013; 41(7): 4307-23.

Guttman M, Rinn JL. Modular regulatory principles of large non-coding RNAs. Nature 2012; 482(7385): 339-46.

Ulitsky I, Bartel DP. lincRNAs: Genomics, evolution, and mechanisms. Cell 2013; 154(1): 26-46.

Wutz A. Gene silencing in X-chromosome inactivation: Advances in understanding facultative heterochromatin formation. Nat Rev Genet 2011; 12(8): 542-53.

Yoon JH, Abdelmohsen K, Gorospe M. Posttranscriptional gene regulation by long noncoding RNA. J Mol Biol 2013; 425(19): 3723-30.

Perin L, Sedrakyan S, Giuliani S, Da Sacco S, Carraro G, Shiri L, et al. Protective effect of human amniotic fluid stem cells in an immunodeficient mouse model of acute tubular necrosis. PLoS One 2010; 5(2): e9357.

Li Y, Syed J, Sugiyama H. RNA-DNA triplex formation by long noncoding RNAs. Cell Chem Biol 2016; 23(11): 1325-33.

Martianov I, Ramadass A, Serra BA, Chow N, Akoulitchev A. Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature 2007; 445(7128): 666-70.

Schmitz KM, Mayer C, Postepska A, Grummt I. Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. Genes Dev 2010; 24(20): 2264-9.

Latos PA, Pauler FM, Koerner MV, Senergin HB, Hudson QJ, Stocsits RR, et al. Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science 2012; 338(6113): 1469-72.

Petruk S, Sedkov Y, Riley KM, Hodgson J, Schweisguth F, Hirose S, et al. Transcription of bxd noncoding RNAs promoted by trithorax represses Ubx in cis by transcriptional interference. Cell 2006; 127(6): 1209-21.

Engreitz JM, Haines JE, Perez EM, Munson G, Chen J, Kane M, et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature 2016; 539(7629): 452-5.

Lee N, Moss WN, Yario TA, Steitz JA. EBV noncoding RNA binds nascent RNA to drive host PAX5 to viral DNA. Cell 2015; 160(4): 607-18.

Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature 2013; 495(7441): 384-8.

Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3' UTRs via Alu elements. Nature 2011; 470(7333): 284-8.

Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 2011; 472(7341): 120-4.

Carrieri C, Cimatti L, Biagioli M, Beugnet A, Zucchelli S, Fedele S, et al. Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature 2012; 491(7424): 454-7.

Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, et al. 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.

Noori-Daloii MR, Eshaghkhani Y. lncRNAs: Significance and function mechanisms. Med Sci J Islamic Azad Univ Tehran Med Branch 2015; 25(2): 79-94.

Kelley D, Rinn J. Transposable elements reveal a stem cell-specific class of long noncoding RNAs.

Genome Biol 2012; 13(11): R107.

Pontier DB, Gribnau J. Xist regulation and function explored. Hum Genet 2011; 130(2): 223-36.

Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 2008; 322(5902): 750-6.

Reik W, Murrell A. Genomic imprinting. Silence across the border. Nature 2000; 405(6785): 408-9.

Li Y, Sasaki H. Genomic imprinting in mammals: Its life cycle, molecular mechanisms and reprogramming. Cell Res 2011; 21(3): 466-73.

Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 2007; 129(7): 1311-23.

Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea MD, et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A 2009; 106(28): 11667-72.

Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 2010; 329(5992): 689-93.

Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 2010; 464(7291): 1071-6.

Lal A, Thomas MP, Altschuler G, Navarro F, O'Day E, Li XL, et al. Capture of microRNA-bound mRNAs identifies the tumor suppressor miR-34a as a regulator of growth factor signaling. PLoS Genet 2011; 7(11): e1002363.

Mohammad F, Mondal T, Kanduri C. Epigenetics of imprinted long non-coding RNAs. Epigenetics 2009; 4(5): 277-86.

Congrains A, Kamide K, Ohishi M, Rakugi H. ANRIL: Molecular mechanisms and implications in human health. Int J Mol Sci 2013; 14(1): 1278-92.

Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 2010; 39(6): 925-38.

Leucci E, Patella F, Waage J, Holmstrom K, Lindow M, Porse B, et al. microRNA-9 targets the long non-coding RNA MALAT1 for degradation in the nucleus. Sci Rep 2013; 3: 2535.

Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, et al. A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell 2014; 25(5): 666-81.

Hu W, Yuan B, Flygare J, Lodish HF. Long noncoding RNA-mediated anti-apoptotic activity in murine erythroid terminal differentiation. Genes Dev 2011; 25(24): 2573-8.

Vignjevic S, Budec M, Markovic D, Dikic D, Mitrovic O, Diklic M, et al. Glucocorticoid receptor mediates the expansion of splenic late erythroid progenitors during chronic psychological stress. J Physiol Pharmacol 2015; 66(1): 91-100.

Paralkar VR, Weiss MJ. A new 'Linc' between noncoding RNAs and blood development. Genes Dev 2011; 25(24): 2555-8.

Johnson R, Teh CH, Jia H, Vanisri RR, Pandey T, Lu ZH, et al. Regulation of neural macroRNAs by the transcriptional repressor REST. RNA 2009; 15(1): 85-96.

Motterle A, Pu X, Wood H, Xiao Q, Gor S, Ng FL, et al. Functional analyses of coronary artery disease associated variation on chromosome 9p21 in vascular smooth muscle cells. Hum Mol Genet 2012; 21(18): 4021-9.

Johnson AD, Hwang SJ, Voorman A, Morrison A, Peloso GM, Hsu YH, et al. Resequencing and clinical associations of the 9p21.3 region: A comprehensive investigation in the Framingham heart study. Circulation 2013; 127(7): 799-810.

Ishii N, Ozaki K, Sato H, Mizuno H, Saito S, Takahashi A, et al. Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction. J Hum Genet 2006; 51(12): 1087-99.

Kumarswamy R, Bauters C, Volkmann I, Maury F, Fetisch J, Holzmann A, et al. Circulating long noncoding RNA, LIPCAR, predicts survival in patients with heart failure. Circ Res 2014; 114(10): 1569-75.

Friese MA, Fugger L. Pathogenic CD8(+) T cells in multiple sclerosis. Ann Neurol 2009; 66(2): 132-41.

Abarrategui I, Krangel MS. Noncoding transcription controls downstream promoters to regulate T-cell receptor alpha recombination. EMBO J 2007; 26(20): 4380-90.

Hafler DA, Compston A, Sawcer S, Lander ES, Daly

MJ, De Jager PL, et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007; 357(9): 851-62.

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.

Tsunoda I, Fujinami RS. Neuropathogenesis of Theiler's murine encephalomyelitis virus infection, an animal model for multiple sclerosis. J Neuroimmune Pharmacol 2010; 5(3): 355-69.

Sartori DA, Chan DW. Biomarkers in prostate cancer: What's new? Curr Opin Oncol 2014; 26(3): 259-64.

Akers JC, Gonda D, Kim R, Carter BS, Chen CC. Biogenesis of extracellular vesicles (EV): Eexosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neurooncol 2013; 113(1): 1-11.

Tang H, Wu Z, Zhang J, Su B. Salivary lncRNA as a potential marker for oral squamous cell carcinoma diagnosis. Mol Med Rep 2013; 7(3): 761-6.

de la Taille A. Progensa PCA3 test for prostate cancer detection. Expert Rev Mol Diagn 2007; 7(5): 491-7.

Han Y, Liu Y, Nie L, Gui Y, Cai Z. Inducing cell proliferation inhibition, apoptosis, and motility reduction by silencing long noncoding ribonucleic acid metastasis-associated lung adenocarcinoma transcript 1 in urothelial carcinoma of the bladder. Urology 2013; 81(1): 209-7.

Qi P, Xu MD, Ni SJ, Shen XH, Wei P, Huang D, et al. Down-regulation of ncRAN, a long non-coding RNA, contributes to colorectal cancer cell migration and invasion and predicts poor overall survival for colorectal cancer patients. Mol Carcinog 2015; 54(9): 742-50.

Ono H, Motoi N, Nagano H, Miyauchi E, Ushijima M, Matsuura M, et al. Long noncoding RNA HOTAIR is relevant to cellular proliferation, invasiveness, and clinical relapse in small-cell lung cancer. Cancer Med 2014; 3(3): 632-42.


  • There are currently no refbacks.

Creative Commons Attribution-NonCommercial 4.0

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.