Modeling Long ncRNA-Mediated Regulation in the Mammalian Cell Cycle

  • Jomar F. RabajanteEmail author
  • Ricardo C. H. del Rosario
Part of the Methods in Molecular Biology book series (MIMB, volume 1912)


Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that are not translated into proteins. They have recently gained widespread attention due to the finding that tens of thousands of lncRNAs reside in the human genome, and due to an increasing number of lncRNAs that are found to be associated with disease. Some lncRNAs, including disease-associated ones, play different roles in regulating the cell cycle. Mathematical models of the cell cycle have been useful in better understanding this biological system, such as how it could be robust to some perturbations and how the cell cycle checkpoints could act as a switch. Here, we discuss mathematical modeling techniques for studying lncRNA regulation of the mammalian cell cycle. We present examples on how modeling via network analysis and differential equations can provide novel predictions toward understanding cell cycle regulation in response to perturbations such as DNA damage.

Key words

lncRNA Cell cycle Mathematical model Regulation Networks DNA damage 



This work is dedicated to the memory of Dr. Baltazar D. Aguda. JFR is supported by the PCARI-CHED IHITM 2017-018 project: Glycoproteomics of Filipino lung cancer cell lines for biomarker discovery and anti-cancer screening of natural products.


  1. 1.
    Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem 81:145–166CrossRefGoogle Scholar
  2. 2.
    Toth KF, Hannon G (2012) Non-coding RNAs as regulators of transcription and genome organization. In: Genome organization and function in the cell nucleus. Wiley-VCH Verlag GmbH & Co., Weinheim. CrossRefGoogle Scholar
  3. 3.
    Wapinski O, Chang HY (2011) Long noncoding RNAs and human disease. Trends Cell Biol 21:354–361CrossRefGoogle Scholar
  4. 4.
    Schmitt AM, Chang HY (2016) Long noncoding RNAs in cancer pathways. Cancer Cell 29:452–463CrossRefGoogle Scholar
  5. 5.
    Wilusz JE, Sunwoo H, Spector DL (2009) Long noncoding RNAs: functional surprises from the RNA world. Genes Dev 23:1494–1504CrossRefGoogle Scholar
  6. 6.
    Perry RB-T, Ulitsky I (2016) The functions of long noncoding RNAs in development and stem cells. Development 143:3882–3894CrossRefGoogle Scholar
  7. 7.
    Marchese FP, Raimondi I, Huarte M (2017) The multidimensional mechanisms of long noncoding RNA function. Genome Biol 18:206CrossRefGoogle Scholar
  8. 8.
    Derrien T, Johnson R, Bussotti G et al (2012) The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression. Genome Res 22:1775–1789CrossRefGoogle Scholar
  9. 9.
    Ziegler C, Kretz M (2017) The More the Merrier—complexity in long non-coding RNA Loci. Front Endocrinol 8:90CrossRefGoogle Scholar
  10. 10.
    Kopp F, Mendell JT (2018) Functional classification and experimental dissection of long noncoding RNAs. Cell 172:393–407CrossRefGoogle Scholar
  11. 11.
    Zhang J, Zhang Z, Wang Z, Liu Y, Deng L (2017) Ontological function annotation of long non-coding RNAs through hierarchical multi-label classification. Bioinformatics 34:1750–1757CrossRefGoogle Scholar
  12. 12.
    Wang KC, Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 43:904–914CrossRefGoogle Scholar
  13. 13.
    St Laurent G, Wahlestedt C, Kapranov P (2015) The Landscape of long noncoding RNA classification. Trends Genet 31:239–251CrossRefGoogle Scholar
  14. 14.
    Mattick JS, Rinn JL (2015) Discovery and annotation of long noncoding RNAs. Nat Struct Mol Biol 22:5–7CrossRefGoogle Scholar
  15. 15.
    Ren K, Li Y, Lu H, Li Z, Li Z, Wu K, Li Z, Han X (2016) Long noncoding RNA HOTAIR controls cell cycle by functioning as a competing endogenous RNA in Esophageal squamous cell carcinoma. Transl Oncol 9:489–497CrossRefGoogle Scholar
  16. 16.
    Zhang X, Weissman SM, Newburger PE (2014) Long intergenic non-coding RNA HOTAIRM1 regulates cell cycle progression during myeloid maturation in NB4 human promyelocytic leukemia cells. RNA Biol 11:777–787CrossRefGoogle Scholar
  17. 17.
    Sahu A, Singhal U, Chinnaiyan AM (2015) Long noncoding RNAs in cancer: from function to translation. Trends Cancer 1:93–109CrossRefGoogle Scholar
  18. 18.
    Aguda BD (2005) Modeling the cell division cycle. In: Lect. Notes Math. Springer-Verlag, Berlin, pp 1–22Google Scholar
  19. 19.
    Ferrell JE, Tsai TY-C, Yang Q (2011) Modeling the cell cycle: why do certain circuits oscillate? Cell 144:874–885CrossRefGoogle Scholar
  20. 20.
    Weis MC, Avva J, Jacobberger JW, Sreenath SN (2014) A data-driven, mathematical model of mammalian cell cycle regulation. PLoS One 9:e97130CrossRefGoogle Scholar
  21. 21.
    Heldt FS, Barr AR, Cooper S, Bakal C, Novák B (2018) A comprehensive model for the proliferation–quiescence decision in response to endogenous DNA damage in human cells. Proc Natl Acad Sci U S A 115:2532–2537CrossRefGoogle Scholar
  22. 22.
    Aguda BD (1999) A quantitative analysis of the kinetics of the G2 DNA damage checkpoint system. Proc Natl Acad Sci U S A 96:11352–11357CrossRefGoogle Scholar
  23. 23.
    Iwamoto K, Tashima Y, Hamada H, Eguchi Y, Okamoto M (2008) Mathematical modeling and sensitivity analysis of G1/S phase in the cell cycle including the DNA-damage signal transduction pathway. Biosystems 94:109–117CrossRefGoogle Scholar
  24. 24.
    Iwamoto K, Hamada H, Eguchi Y, Okamoto M (2011) Mathematical modeling of cell cycle regulation in response to DNA damage: exploring mechanisms of cell-fate determination. Biosystems 103:384–391CrossRefGoogle Scholar
  25. 25.
    Aguda BD, Algar CK (2003) A structural analysis of the qualitative networks regulating the cell cycle and apoptosis. Cell Cycle 2:538–543CrossRefGoogle Scholar
  26. 26.
    Zhao J, Liu Y, Zhang W, Zhou Z, Wu J, Cui P, Zhang Y, Huang G (2015) Long non-coding RNA Linc00152 is involved in cell cycle arrest, apoptosis, epithelial to mesenchymal transition, cell migration and invasion in gastric cancer. Cell Cycle 14:3112–3123CrossRefGoogle Scholar
  27. 27.
    Mazar J, Rosado A, Shelley J, Marchica J, Westmoreland TJ (2017) The long non-coding RNA GAS5 differentially regulates cell cycle arrest and apoptosis through activation of BRCA1 and p53 in human neuroblastoma. Oncotarget 8:6589–6607CrossRefGoogle Scholar
  28. 28.
    Kitagawa M, Kitagawa K, Kotake Y, Niida H, Ohhata T (2013) Cell cycle regulation by long non-coding RNAs. Cell Mol Life Sci 70:4785–4794CrossRefGoogle Scholar
  29. 29.
    Kutter C, Watt S, Stefflova K, Wilson MD, Goncalves A, Ponting CP, Odom DT, Marques AC (2012) Rapid turnover of long noncoding RNAs and the evolution of gene expression. PLoS Genet 8:e1002841CrossRefGoogle Scholar
  30. 30.
    Szcześniak MW, Makałowska I (2016) lncRNA-RNA interactions across the human transcriptome. PLoS One 11:e0150353CrossRefGoogle Scholar
  31. 31.
    Forouzmand E, Owens NDL, Blitz IL, Paraiso KD, Khokha MK, Gilchrist MJ, Xie X, Cho KWY (2017) Developmentally regulated long non-coding RNAs in Xenopus tropicalis. Dev Biol 426:401–408CrossRefGoogle Scholar
  32. 32.
    Aguda B, Friedman A (2008) Models of cellular regulation. Oxford University Press, New YorkCrossRefGoogle Scholar
  33. 33.
    Gauthier JH, Pohl PI (2011) A general framework for modeling growth and division of mammalian cells. BMC Syst Biol 5:3CrossRefGoogle Scholar
  34. 34.
    Singhania R, Sramkoski RM, Jacobberger JW, Tyson JJ (2011) A hybrid model of mammalian cell cycle regulation. PLoS Comput Biol 7:e1001077CrossRefGoogle Scholar
  35. 35.
    Aguda BD, Goryachev AB (2007) From pathways databases to network models of switching behavior. PLoS Comput Biol 3:e152CrossRefGoogle Scholar
  36. 36.
    Müller J, Kuttler C (2015) Methods and models in mathematical biology. Springer, BerlinCrossRefGoogle Scholar
  37. 37.
    Bernot G, Comet J-P, Richard A, Chaves M, Gouzé J-L, Dayan F (2013) Modeling and analysis of gene regulatory networks. In: Cazals F, Kornprobst P (eds) Modeling in computational biology and biomedicine. Springer, Berlin, pp 47–80CrossRefGoogle Scholar
  38. 38.
    Jalali S, Kapoor S, Sivadas A, Bhartiya D, Scaria V (2015) Computational approaches towards understanding human long non-coding RNA biology. Bioinformatics 31:2241–2251CrossRefGoogle Scholar
  39. 39.
    Milo R (2002) Network Motifs: simple building blocks of complex networks. Science 298:824–827CrossRefGoogle Scholar
  40. 40.
    Alon U (2007) Network motifs: theory and experimental approaches. Nat Rev Genet 8:450–461CrossRefGoogle Scholar
  41. 41.
    Junker BH, Schreiber F (2008) Analysis of biological networks. Wiley-Interscience, Hoboken, NJCrossRefGoogle Scholar
  42. 42.
    Barabasi A-L (2016) Network science. Cambridge University Press, CambridgeGoogle Scholar
  43. 43.
    Hecker M, Lambeck S, Toepfer S, van Someren E, Guthke R (2009) Gene regulatory network inference: data integration in dynamic models—a review. Biosystems 96:86–103CrossRefGoogle Scholar
  44. 44.
    Marbach D, Costello JC, Küffner R et al (2012) Wisdom of crowds for robust gene network inference. Nat Methods 9:796–804CrossRefGoogle Scholar
  45. 45.
    Creixell P, Reimand J et al (2015) Pathway and network analysis of cancer genomes. Nat Methods 12:615–621CrossRefGoogle Scholar
  46. 46.
    Sun M, Gadad SS, Kim D-S, 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 59:698–711CrossRefGoogle Scholar
  47. 47.
    Liu F, Zhang S-W, Guo W-F, Wei Z-G, Chen L (2016) Inference of gene regulatory network based on local Bayesian networks. PLoS Comput Biol 12:e1005024CrossRefGoogle Scholar
  48. 48.
    Feng N, Ching T, Wang Y et al (2016) Analysis of microarray data on gene expression and methylation to identify long non-coding RNAs in non-small cell lung cancer. Sci Rep 6:37233CrossRefGoogle Scholar
  49. 49.
    Filkov V (2005) Identifying gene regulatory networks from gene expression data. In: Handbook of computational molecular biology. CRC Press, Boca Raton, FL, pp 1–29Google Scholar
  50. 50.
    Leal LG, López C, López-Kleine L (2014) Construction and comparison of gene co-expression networks shows complex plant immune responses. PeerJ 2:e610CrossRefGoogle Scholar
  51. 51.
    Zhang L, Feng XK, Ng YK, Li SC (2016) Reconstructing directed gene regulatory network by only gene expression data. BMC Genomics 17:430CrossRefGoogle Scholar
  52. 52.
    Zhang Y, Huang H, Zhang D, Qiu J, Yang J, Wang K, Zhu L, Fan J, Yang J (2017) A review on recent computational methods for predicting noncoding RNAs. Biomed Res Int 2017:1–14Google Scholar
  53. 53.
    del Rosario RCH, Damasco JRCG, Aguda BD (2016) MicroRNA inhibition fine-tunes and provides robustness to the restriction point switch of the cell cycle. Sci Rep 6:32823CrossRefGoogle Scholar
  54. 54.
    Foster SS, De S, Johnson LK, Petrini JHJ, Stracker TH (2012) Cell cycle- and DNA repair pathway-specific effects of apoptosis on tumor suppression. Proc Natl Acad Sci U S A 109:9953–9958CrossRefGoogle Scholar
  55. 55.
    Nowsheen S, Yang ES (2012) The intersection between DNA damage response and cell death pathways. Exp Oncol 34:243–254PubMedPubMedCentralGoogle Scholar
  56. 56.
    Ding L, Wang M, Sun D, Li A (2018) TPGLDA: Novel prediction of associations between lncRNAs and diseases via lncRNA-disease-gene tripartite graph. Sci Rep 8:1065CrossRefGoogle Scholar
  57. 57.
    Yang X, Gao L, Guo X, Shi X, Wu H, Song F, Wang B (2014) A network based method for analysis of lncRNA-disease associations and prediction of lncRNAs implicated in diseases. PLoS One 9:e87797CrossRefGoogle Scholar
  58. 58.
    Chen X, Yan CC, Zhang X, You Z-H (2016) Long non-coding RNAs and complex diseases: from experimental results to computational models. Brief Bioinform 18:558–576PubMedCentralGoogle Scholar
  59. 59.
    Gu C, Liao B, Li X, Cai L, Li Z, Li K, Yang J (2017) Global network random walk for predicting potential human lncRNA-disease associations. Sci Rep 7:12442CrossRefGoogle Scholar
  60. 60.
    Huang Y-A, Chan KCC, You Z-H (2018) Constructing prediction models from expression profiles for large scale lncRNA–miRNA interaction profiling. Bioinformatics 34:812–819CrossRefGoogle Scholar
  61. 61.
    Bloomingdale P, Nguyen VA, Niu J, Mager DE (2018) Boolean network modeling in systems pharmacology. J Pharmacokinet Pharmacodyn 45:159–180CrossRefGoogle Scholar
  62. 62.
    Thieffry D (2007) Dynamical roles of biological regulatory circuits. Brief Bioinform 8:220–225CrossRefGoogle Scholar
  63. 63.
    Yeger-Lotem E, Sattath S, Kashtan N, Itzkovitz S, Milo R, Pinter RY, Alon U, Margalit H (2004) Network motifs in integrated cellular networks of transcription-regulation and protein-protein interaction. Proc Natl Acad Sci U S A 101:5934–5939CrossRefGoogle Scholar
  64. 64.
    Voit EO, Radivoyevitch T (2000) Biochemical systems analysis of genome-wide expression data. Bioinformatics 16:1023–1037CrossRefGoogle Scholar
  65. 65.
    Kikuchi S, Tominaga D, Arita M, Takahashi K, Tomita M (2003) Dynamic modeling of genetic networks using genetic algorithm and S-system. Bioinformatics 19:643–650CrossRefGoogle Scholar
  66. 66.
    Voit EO (2013) Biochemical systems theory: a review. ISRN Biomath 2013:1–53CrossRefGoogle Scholar
  67. 67.
    Chowdhury AR, Chetty M, Evans R (2015) Stochastic S-system modeling of gene regulatory network. Cogn Neurodyn 9:535–547CrossRefGoogle Scholar
  68. 68.
    Voit EO, Martens HA, Omholt SW (2015) 150 Years of the mass action law. PLoS Comput Biol 11:e1004012CrossRefGoogle Scholar
  69. 69.
    Rabajante JF, Talaue CO (2015) Equilibrium switching and mathematical properties of nonlinear interaction networks with concurrent antagonism and self-stimulation. Chaos Solitons Fractals 73:166–182CrossRefGoogle Scholar
  70. 70.
    Marchese FP, Huarte M (2017) A long noncoding RNA in DNA replication and chromosome dynamics. Cell Cycle 16:151–152CrossRefGoogle Scholar
  71. 71.
    Rabajante JF, Babierra AL (2015) Branching and oscillations in the epigenetic landscape of cell-fate determination. Prog Biophys Mol Biol 117:240–249CrossRefGoogle Scholar
  72. 72.
    Sauer T (2012) Numerical analysis, 2nd edn. Pearson, BostonGoogle Scholar
  73. 73.
    Dhooge A, Govaerts W, Kuznetsov YA (2003) MATCONT: A MATLAB package for numerical bifurcation analysis of ODEs. ACM Trans Math Softw 29:141–164CrossRefGoogle Scholar
  74. 74.
    Allen E (2007) Modeling with Itô stochastic differential equations. Springer, DordrechtGoogle Scholar
  75. 75.
    Cardelli L, Csikász-Nagy A, Dalchau N, Tribastone M, Tschaikowski M (2016) Noise reduction in complex biological switches. Sci Rep 6:20214. CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Ulitsky I (2016) Evolution to the rescue: using comparative genomics to understand long non-coding RNAs. Nat Rev Genet 17:601–614CrossRefGoogle Scholar
  77. 77.
    Joung J, Engreitz JM, Konermann S et al (2017) Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood. Nature 548:343–346CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Jomar F. Rabajante
    • 1
    Email author
  • Ricardo C. H. del Rosario
    • 2
  1. 1.Institute of Mathematical Sciences and PhysicsUniversity of the Philippines Los BañosLagunaPhilippines
  2. 2.Stanley Center for Psychiatric ResearchBroad Institute of MIT and HarvardCambridgeUSA

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