Skip to main content

Advertisement

Log in

Metapath-Based Deep Convolutional Neural Network for Predicting miRNA-Target Association on Heterogeneous Network

  • Original research article
  • Published:
Interdisciplinary Sciences: Computational Life Sciences Aims and scope Submit manuscript

Abstract

Predicting the interactions between microRNAs (miRNAs) and target genes is of great significance for understanding the regulatory mechanism of miRNA and treating complex diseases. The emergence of large-scale, heterogeneous biological networks has offered unprecedented opportunities for revealing miRNA-associated target genes. However, there are still some limitations about automatically learn the feature information of the network in the existing methods. Since network representation learning can self-adaptively capture structure information of the network, we propose a framework based on heterogeneous network representation, MDCNN (Metapath-Based Deep Convolutional Neural Network), to predict the associations between miRNAs and target genes. MDCNN samples the paths between the node pairs in the form of meta-path based on the heterogeneous information network (HIN) about miRNAs and target genes. Then the node feature and the path feature which is learned by the Deep Convolutional Neural Network (DCNN) are spliced together as the representation of the miRNA-target gene, to predict the miRNA-target gene interactions. The experiment results indicate that the performance of MDCNN outperforms other methods in multiple validation metrics by fivefold cross validation. We set an ablation study to identify the necessity of miRNA similarity and target gene similarity for improving the prediction ability of MDCNN. The case studies on hsa-miR-26b-5p and CDKN1A further demonstrates that MDCNN can successfully predict potential miRNA-target gene interactions.

Graphic abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297. https://doi.org/10.1016/S0092-8674(04)00045-5

    Article  CAS  PubMed  Google Scholar 

  2. Ambros V (2004) The functions of animal microRNAs. Nature 431(7006):350–355. https://doi.org/10.1038/nature02871

    Article  CAS  PubMed  Google Scholar 

  3. Xia W, Cao G, Shao N (2009) Progress in miRNA target prediction and identification. Sci China Ser C Life Sci 52(12):1123–1130. https://doi.org/10.1007/s11427-009-0159-4

    Article  CAS  Google Scholar 

  4. Lu M, Zhang Q, Deng M, Miao J, Guo Y, Gao W, Cui Q (2008) An analysis of human microRNA and disease associations. PLoS ONE 3(10):e3420. https://doi.org/10.1371/journal.pone.0003420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kozomara A, Birgaoanu M, Griffiths-Jones S (2019) miRBase: from microRNA sequences to function. Nucleic Acids Res 47(D1):D155–D162. https://doi.org/10.1093/nar/gky1141

    Article  CAS  PubMed  Google Scholar 

  6. Wei L, Huang Y, Qu Y, Jiang Y, Zou Q (2012) Computational analysis of miRNA target identification. Curr Bioinform 7(4):512–525. https://doi.org/10.2174/157489312803900974

    Article  CAS  Google Scholar 

  7. Lewis BP, Shih I-H, Jones-Rhoades MW, Bartel DP, Burge CB (2003) Prediction of mammalian microRNA targets. Cell 115(7):787–798. https://doi.org/10.1016/S0092-8674(03)01018-3

    Article  CAS  PubMed  Google Scholar 

  8. John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS (2004) Human microRNA targets. PLoS Biol 2(11):e363. https://doi.org/10.1371/journal.pbio.0020363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kertesz M, Iovino N, Unnerstall U, Gaul U, Segal E (2007) The role of site accessibility in microRNA target recognition. Nat Genet 39(10):1278–1284. https://doi.org/10.1038/ng2135

    Article  CAS  PubMed  Google Scholar 

  10. Opitz D, Maclin R (1999) Popular ensemble methods: an empirical study. J Artif Intell Res 11:169–198. https://doi.org/10.1613/jair.614

    Article  Google Scholar 

  11. Cortes C, Vapnik V (1995) Support-vector networks. Mach Learn 20(3):273–297. https://doi.org/10.1007/BF00994018

    Article  Google Scholar 

  12. Kim S-K, Nam J-W, Rhee J-K, Lee W-J, Zhang B-T (2006) miTarget: microRNA target gene prediction using a support vector machine. BMC Bioinform 7(1):1–12. https://doi.org/10.1186/1471-2105-7-411

    Article  CAS  Google Scholar 

  13. Reyes-Herrera PH, Ficarra E, Acquaviva A, Macii E (2011) miREE: miRNA recognition elements ensemble. BMC Bioinform 12(1):454. https://doi.org/10.1186/1471-2105-12-454

    Article  Google Scholar 

  14. Ding J, Li X, Hu H (2016) TarPmiR: a new approach for microRNA target site prediction. Bioinformatics 32(18):2768–2775. https://doi.org/10.1093/bioinformatics/btw318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chen H, Perozzi B, Al-Rfou R, Skiena S (2018) A tutorial on network embeddings. arXiv preprint arXiv:1808.02590 [v1]

  16. Perozzi B, Al-Rfou R, Skiena S (2014) DeepWalk: online learning of social representations. ACM. https://doi.org/10.1145/2623330.2623732

    Article  Google Scholar 

  17. Tang J, Qu M, Wang M, Zhang M, Yan J, Mei Q (2015) LINE: large-scale information network embedding. WWW. https://doi.org/10.1145/2736277.2741093

    Article  Google Scholar 

  18. Grover A, Leskovec J (2016) node2vec: scalable feature learning for networks. ACM. https://doi.org/10.1145/2939672.2939754

    Article  Google Scholar 

  19. Cao S, Wei L, Xu Q (2015) GraRep: learning graph representations with global structural information. ACM. https://doi.org/10.1145/2806416

    Article  Google Scholar 

  20. Dong Y, Chawla NV, Swami A (2017) metapath2vec: scalable representation learning for heterogeneous networks. ACM. DOI 10(1145/3097983):3098036

    Google Scholar 

  21. Fu TY, Lee WC, Zhen L (2017) HIN2Vec: explore meta-paths in heterogeneous information networks for representation learning. ACM. DOI 10(1145/3132847):3132953

    Google Scholar 

  22. do Valle ÍF, Menichetti G, Simonetti G, Bruno S, Zironi I, Durso DF, Mombach JC, Martinelli G, Castellani G, Remondini D (2018) Network integration of multi-tumour omics data suggests novel targeting strategies. Nat Commun 9(1):1–10. https://doi.org/10.1038/s41467-018-06992-7

    Article  CAS  Google Scholar 

  23. Wang L, Nie R, Yu Z, Xin R, Zheng C, Zhang Z, Zhang J, Cai J (2020) An interpretable deep-learning architecture of capsule networks for identifying cell-type gene expression programs from single-cell RNA-sequencing data. Nat Mach Intell 2(11):693–703. https://doi.org/10.1038/s42256-020-00244-4

    Article  Google Scholar 

  24. Shen C, Luo J, Ouyang W, Ding P, Wu H (2020) Identification of small molecule–miRNA associations with graph regularization techniques in heterogeneous networks. J Chem Inf Model 60(12):6709–6721. https://doi.org/10.1021/acs.jcim.0c00975

    Article  CAS  PubMed  Google Scholar 

  25. Shen C, Luo J, Lai Z, Ding P (2020) Multiview joint learning-based method for identifying small-molecule-associated MiRNAs by integrating pharmacological, genomics, and network knowledge. J Chem Inf Model 60(8):4085–4097. https://doi.org/10.1021/acs.jcim.0c00244

    Article  CAS  PubMed  Google Scholar 

  26. Luo J, Shen C, Lai Z, Cai J, Ding P (2020) Incorporating clinical, chemical and biological information for predicting small molecule-microRNA associations based on non-negative matrix factorization. IEEE/ACM Trans Comput Biol Bioinform PP(99):1–1. https://doi.org/10.1109/TCBB.2020.2975780

    Article  Google Scholar 

  27. Liu Y, Luo J, Ding P (2018) Inferring MicroRNA targets based on restricted Boltzmann machines. IEEE J Biomed Health Inform 23(1):427–436. https://doi.org/10.1109/JBHI.2018.2814609

    Article  PubMed  Google Scholar 

  28. Xie W, Luo J, Pan C, Liu Y (2020) SG-LSTM-FRAME: a computational frame using sequence and geometrical information via LSTM to predict miRNA–gene associations. Brief Bioinform 22(2):2032–2042. https://doi.org/10.1093/bib/bbaa022

    Article  CAS  Google Scholar 

  29. Zhu Q, Fan Y, Pan X (2020) Fusing multiple biological networks to effectively predict miRNA-disease associations. Curr Bioinform 16(3):371–384. https://doi.org/10.2174/1574893615999200715165335

    Article  CAS  Google Scholar 

  30. Shen C, Luo J, Ouyang W, Ding P, Chen X (2020) IDDkin: Network-based influence deep diffusion model for enhancing prediction of kinase inhibitors. Bioinformatics 36(22–23):5481–5491. https://doi.org/10.1093/bioinformatics/btaa1058

    Article  CAS  Google Scholar 

  31. Sun Y, Han J, Yan X, Yu PS, Wu T (2011) Pathsim: meta path-based top-k similarity search in heterogeneous information networks. Proc VLDB Endow 4(11):992–1003. https://doi.org/10.14778/3402707.3402736

    Article  Google Scholar 

  32. Sohyun H, Yeong KC, Yang S, Eiru K, Traver H, Marcotte EM, Insuk L (2018) HumanNet v2: human gene networks for disease research. Nucleic Acids Res D1:D573–D580. https://doi.org/10.1093/nar/gky1126

    Article  CAS  Google Scholar 

  33. Chou C-H, Shrestha S, Yang C-D, Chang N-W, Lin Y-L, Liao K-W, Huang W-C, Sun T-H, Tu S-J, Lee W-H (2018) miRTarBase update 2018: a resource for experimentally validated microRNA-target interactions. Nucleic Acids Res 46(D1):D296–D302. https://doi.org/10.1093/nar/gkx1067

    Article  CAS  PubMed  Google Scholar 

  34. Needleman SB, Wunsch CD (1970) A general method applicable to the search for similarities in the amino acid sequence of two proteins. J Mol Biol 48(3):443–453. https://doi.org/10.1016/0022-2836(70)90057-4

    Article  CAS  PubMed  Google Scholar 

  35. Khan A, Sohail A, Zahoora U, Qureshi AS (2020) A survey of the recent architectures of deep convolutional neural networks. Artif Intell Rev 53(8):5455–5516. https://doi.org/10.1007/s10462-020-09825-6

    Article  Google Scholar 

  36. Kingma DP, Ba J (2014) Adam: a method for stochastic optimization. arXiv preprint arXiv:1412.6980 [v4]

  37. Liu X-X, Li X-J, Zhang B, Liang Y-J, Zhou C-X, Cao D-X, He M, Chen G-Q, He J-R, Zhao Q (2011) MicroRNA-26b is underexpressed in human breast cancer and induces cell apoptosis by targeting SLC7A11. FEBS Lett 585(9):1363–1367. https://doi.org/10.1016/j.febslet.2011.04.018

    Article  CAS  PubMed  Google Scholar 

  38. Fornari F, Milazzo M, Chieco P, Negrini M, Marasco E, Capranico G, Mantovani V, Marinello J, Sabbioni S, Callegari E (2012) In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2. J Pathol 227(3):275–285. https://doi.org/10.1002/path.3995

    Article  CAS  PubMed  Google Scholar 

  39. Grilli A, Sciandra M, Terracciano M, Picci P, Scotlandi K (2015) Integrated approaches to miRNAs target definition: time-series analysis in an osteosarcoma differentiative model. BMC Med Genom 8(1):34. https://doi.org/10.1186/s12920-015-0106-0

    Article  CAS  Google Scholar 

  40. Chen Z, Wu H, Wang G, Feng Y (2016) Identification of potential candidate genes for hypertensive nephropathy based on gene expression profile. BMC Nephrol 17(1):149. https://doi.org/10.1186/s12882-016-0366-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhao J, Fu W, Liao H, Dai L, Jiang Z, Pan Y, Huang H, Mo Y, Li S, Yang G (2015) The regulatory and predictive functions of miR-17 and miR-92 families on cisplatin resistance of non-small cell lung cancer. BMC Cancer 15(1):1–14. https://doi.org/10.1186/s12885-015-1713-z

    Article  CAS  Google Scholar 

  42. Xu J, Lv H, Zhang B, Xu F, Zhu H, Chen B, Zhu C, Shen J (2019) miR-30b-5p acts as a tumor suppressor microRNA in esophageal squamous cell carcinoma. J Thorac Dis 11(7):3015. https://doi.org/10.21037/jtd.2019.07.50

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work has been supported by the National Natural Science Foundation of China (Grant nos. 62032007, 61873089), Hunan Provincial Innovation Foundation for Postgraduate (Grant no. CX20200436)

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xiangtao Chen.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luo, J., Bao, Y., Chen, X. et al. Metapath-Based Deep Convolutional Neural Network for Predicting miRNA-Target Association on Heterogeneous Network. Interdiscip Sci Comput Life Sci 13, 547–558 (2021). https://doi.org/10.1007/s12539-021-00454-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12539-021-00454-3

Keywords

Navigation