Abstract
DNA-binding proteins (DBPs) have an important role in various regulatory tasks. In recent years, with developing of deep learning, many fields like natural language processing, computer vision and so on have achieve great success. Some great model, for example DeepBind, brought deep learning to motif discovery and also achieve great success in predicting DNA-transcription factor binding, aka motif discovery. But these methods required integrating multiple features with raw DNA sequences such as secondary structure and their performances could be further improved. In this paper, we propose an efficient and simple neural network-based architecture, DBPCNN, integrating conservation scores and epigenomic data to raw DNA sequences for predicting in-vitro DNA protein binding sequence. We show that conservation scores and epigenomic data for raw DNA sequences can significantly improve the overall performance of the proposed model. Moreover, the automatic extraction of the DBA-binding proteins can enhance our understanding of the binding specificities of DBPs. We verify the effectiveness of our model on 20 motif datasets from in-vitro protein binding microarray data. More specifically, the average area under the receiver operator curve (AUC) was improved by 0.58% for conservation scores, 1.29% for MeDIP-seq, 1.20% for histone modifications respectively, and 2.19% for conservation scores, MeDIP-seq and histone modifications together. And the mean average precision (AP) was increased by 0.62% for conservation scores, 1.46% for MeDIP-seq, 1.27% for histone modifications respectively, and 2.29% for conservation scores, MeDIP-seq and histone modifications together.
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References
Lambert, S.A., et al.: The human transcription factors. Cell 172, 650–665 (2018)
Vaquerizas, J.M., Kummerfeld, S.K., Teichmann, S.A., Luscombe, N.M.: A census of human transcription factors: function, expression and evolution. Nat. Rev. Genet. 10, 252 (2009)
Stormo, G.D.J.B.: DNA binding sites: representation and discovery. Bioinformatics 16, 16–23 (2000)
Lee, T.I., Young, R.A.: Transcriptional regulation and its misregulation in disease. Cell 152, 1237–1251 (2013)
Zhu, L., Zhang, H.-B., Huang, D.-S.: Direct AUC optimization of regulatory motifs. Bioinformatics 33, i243–i251 (2017)
Tianyin, Z., Ning, et al.: Quantitative modeling of transcription factor binding specificities using DNA shape. Proc. Natl. Acad. Sci. 112–115 (2015)
Berger, M.F., Philippakis, A.A., Qureshi, A.M., et al.: Compact, universal DNA microarrays to comprehensively determine transcription-factor binding site specificities. Nat. Biotechnol. 24(11), 1429–1435 (2006)
Stormo, G.D., Zhao, Y.: Determining the specificity of protein-DNA interactions. NAT Rev. Genet. 11(11), 751–760 (2010)
Gordân, R., et al.: Genomic regions flanking e-box binding sites influence DNA binding specificity of bHLH transcription factors through DNA shape. Cell Rep. 3, 1093–1104 (2013)
Fletezbrant, C., Lee, D., Mccallion, A.S., Beer, M.: kmer-SVM: a web server for identifying predictive regulatory sequence features in genomic data sets. Nucleic Acids Res. 41, 544–556 (2013)
Shen, Z., Bao, W., Huang, D.: Recurrent neural network for predicting transcription factor binding sites. Sci. Rep. 8, 15270 (2018)
Zhang, Q., Zhu, L., Bao, W., Huang, D.S.: Weakly-supervised convolutional neural network architecture for predicting protein-DNA binding. IEEE/ACM Trans. Comput. Biol. Bioinform. 17(2), 679–689 (2020)
Zhang, Q., Zhu, L., Huang, D.S.: High-order convolutional neural network architecture for predicting DNA-protein binding sites. IEEE/ACM Trans. Comput. Biol. Bioinform. 16(4), 1184–1192 (2019)
Zhang, Q., Shen, Z., Huang, D.-S.: Modeling in-vivo protein-DNA binding by combining multiple-instance learning with a hybrid deep neural network. Sci. Rep. 9, 8484 (2019)
Xu, W., Zhu, L., Huang, D.S.: DCDE: an efficient deep convolutional divergence encoding method for human promoter recognition. IEEE Trans. NanoBioscience 18(2), 136–145 (2019)
Zhang, H., Zhu, L., Huang, D.S.: DiscMLA: an efficient discriminative motif learning algorithm over high-throughput datasets. IEEE/ACM Trans. Comput. Biol. Bioinform. 15(6), 1810–1820 (2018)
Zhang, H., Zhu, L., Huang, D.S.: WSMD: weakly-supervised motif discovery in transcription factor ChIP-seq data. Sci. Rep. 7 (2017). https://doi.org/10.1038/s41598-017-03554-7
Yu, W., Yuan, C.-A., Qin, X., Huang, Z.-K., Shang, L.: Hierarchical attention network for predicting DNA-protein binding sites. In: Huang, D.-S., Jo, K.-H., Huang, Z.-K. (eds.) ICIC 2019. LNCS, vol. 11644, pp. 366–373. Springer, Cham (2019). https://doi.org/10.1007/978-3-030-26969-2_35
Weirauch, M.T., et al.: Evaluation of methods for modeling transcription factor sequence specificity. Nat. Biotechnol. 31, 126–134 (2013)
Alipanahi, B., Delong, A., Weirauch, M.T., Frey, B.J.: Predicting the sequence specificities of DNA-and RNA-binding proteins by deep learning. Nat. Biotechnol. 33, 831–838 (2015)
Zhu, L., Bao, W.Z., Huang, D.S.: Learning TF binding motifs by optimizing fisher exact test score. IEEE/ACM Trans. Comput. Biol. Bioinform. (2017)
Zhu, L., Zhang, H.-B., Huang, D.S.: LMMO: a large margin approach for optimizing regulatory motifs. IEEE/ACM Trans. Comput. Biol. Bioinform. 15(3), 913–925 (2018)
Zhu, L., Zhang, H.-B., Huang, D.-S.: Direct AUC optimization of regulatory motifs. Bioinformatics 33(14), i243–i251 (2017). https://doi.org/10.1093/bioinformatics/btx255
Zhu, L., Guo, W., Deng, S.-P., Huang, D.S.: ChIP-PIT: Enhancing the analysis of ChIP-Seq data using convex-relaxed pair-wise interaction tensor decomposition. IEEE/ACM Trans. Comput. Biol. Bioinform. 13(1), 55–63 (2016)
Guo, W.L., Huang, D.S.: An efficient method to transcription factor binding sites imputation via simultaneous completion of multiple matrices with positional consistency. Mol. Biosyst. 13, 1827–1837 (2017)
Boffelli, D., et al.: Phylogenetic shadowing of primate sequences to find functional regions of the human genome. Science 299(5611), 1391–1394 (2003)
Bpffelli, D., Nobrega, M.A., Rubin, E.M.: Comparative genomics at the vertebrate extremes. Nat. Rev. Genet. 5(6), 456–465 (2004)
McGuire, A.M., Hughes, J.D., Church, G.M.: Conservation of dna regulatory motifs and discovery of new motifs in microbial genomes. Genome Res. 10(6), 744–757 (2000)
Li, H., Rhodius, V., Gross, C., Siggia, E.D.: Identification of the binding sites of regulatory proteins in bacterial genomes. Proc. Natl. Acad. Sci. 99(18), 11772–11777 (2002)
Woolfe, A., et al.: Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol. 3(1), e7 (2004)
Tayara, H., Chong, K.: Improved predicting of the sequence specificities of RNA binding proteins by deep learning. IEEE/ACM Trans. Comput. Biol. Bioinform. (2020)
Jing, F., Zhang, S.-W., Cao, Z., Zhang, S.: Combining sequence and epigenomic data to predict transcription factor binding sites using deep learning. In: Zhang, F., Cai, Z., Skums, P., Zhang, S. (eds.) ISBRA 2018. LNCS, vol. 10847, pp. 241–252. Springer, Cham (2018). https://doi.org/10.1007/978-3-319-94968-0_23
Stewart, A.J., Hannenhalli, S., Plotkin, J.B.: Why transcription factor binding sites are ten nucleotides long. Genetics 192(3), 973–985 (2012)
Glorot, X., Bengio, Y.: Understanding the difficulty of training deep feedforward neural networks. In: International Conference on Artificial Intelligence and Statistics, pp. 249–256 (2010)
Zeiler, M.D.: ADADELTA: an adaptive learning rate method. arXiv abs/1212.5701 (2012)
Rohs, R., West, S.M., Sosinsky, A., Liu, P., Mann, R.S., Honig, B.: The role of DNA shape in protein–DNA recognition. Nature 461, 1248–1253 (2009)
Zhou, T., et al.: Quantitative modeling of transcription factor binding specificities using DNA shape. Proc. Natl. Acad. Sci. U.S.A. 112, 4654–4659 (2015)
Zhang, Q., Shen, Z., Huang, D.: Predicting in-vitro transcription factor binding sites using DNA sequence + shape. IEEE/ACM Trans. Comput. Biol. Bioinform. 1 (2019)
Tsatsaronis, G., Panagiotopoulou, V.: A generalized vector space model for text retrieval based on semantic relatedness. In: Conference of the European Chapter of the Association for Computational Linguistics, pp. 70–78 (2009)
Wang, J., Huang, P., Zhao, H., Zhang, Z., Zhao, B., Lee, D.L.: Billion-scale commodity embedding for E-commerce recommendation in Alibaba. In: Knowledge Discovery and Data Mining, pp. 839–848 (2018)
Wang, D., Zhang, Q., Yuan, C.-A., Qin, X., Huang, Z.-K., Shang, L.: Motif discovery via convolutional networks with K-mer embedding. In: Huang, D.-S., Jo, K.-H., Huang, Z.-K. (eds.) ICIC 2019. LNCS, vol. 11644, pp. 374–382. Springer, Cham (2019). https://doi.org/10.1007/978-3-030-26969-2_36
Zhu, L., Guo, W.-L., Huang, D.S., Lu, C.-Y.: Imputation of ChIP-seq datasets via low rank convex co-embedding. In: 2015 IEEE International Conference on Bioinformatics and Biomedicine (BIBM), pp. 141–144 (2015)
Chen, Z.-H., et al.: Prediction of drug-target interactions from multi-molecular network based on deep walk embedding model. Front. Bioeng. Biotechnol. 8, 338 (2020)
Acknowledgements
This work was supported by the grant of National Key R&D Program of China (No. 2018AAA0100100 & 2018YFA0902600) and partly supported by National Natural Science Foundation of China (Grant nos. 61861146002, 61732012, 61772370, 62002266, 61932008, 61772357, and 62073231) and supported by “BAGUI Scholar” Program and the Scientific & Technological Base and Talent Special Program, GuiKe AD18126015 of the Guangxi Zhuang Autonomous Region of China.
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Xu, Y., Zhang, Q., Chen, Z., Yuan, C., Qin, X., Wu, H. (2021). Using Deep Learning to Predict Transcription Factor Binding Sites Combining Raw DNA Sequence, Evolutionary Information and Epigenomic Data. In: Huang, DS., Jo, KH., Li, J., Gribova, V., Premaratne, P. (eds) Intelligent Computing Theories and Application. ICIC 2021. Lecture Notes in Computer Science(), vol 12838. Springer, Cham. https://doi.org/10.1007/978-3-030-84532-2_35
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