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Current Genomics

Editor-in-Chief

ISSN (Print): 1389-2029
ISSN (Online): 1875-5488

General Research Article

WITMSG: Large-scale Prediction of Human Intronic m6A RNA Methylation Sites from Sequence and Genomic Features

Author(s): Lian Liu, Xiujuan Lei*, Jia Meng and Zhen Wei*

Volume 21, Issue 1, 2020

Page: [67 - 76] Pages: 10

DOI: 10.2174/1389202921666200211104140

Price: $65

Abstract

Introduction: N6-methyladenosine (m6A) is one of the most widely studied epigenetic modifications. It plays important roles in various biological processes, such as splicing, RNA localization and degradation, many of which are related to the functions of introns. Although a number of computational approaches have been proposed to predict the m6A sites in different species, none of them were optimized for intronic m6A sites. As existing experimental data overwhelmingly relied on polyA selection in sample preparation and the intronic RNAs are usually underrepresented in the captured RNA library, the accuracy of general m6A sites prediction approaches is limited for intronic m6A sites prediction task.

Methodology: A computational framework, WITMSG, dedicated to the large-scale prediction of intronic m6A RNA methylation sites in humans has been proposed here for the first time. Based on the random forest algorithm and using only known intronic m6A sites as the training data, WITMSG takes advantage of both conventional sequence features and a variety of genomic characteristics for improved prediction performance of intron-specific m6A sites.

Results and Conclusion: It has been observed that WITMSG outperformed competing approaches (trained with all the m6A sites or intronic m6A sites only) in 10-fold cross-validation (AUC: 0.940) and when tested on independent datasets (AUC: 0.946). WITMSG was also applied intronome-wide in humans to predict all possible intronic m6A sites, and the prediction results are freely accessible at http://rnamd.com/intron/.

Keywords: m6A, intron, site prediction, sequence features, genomic features, RNA methylation.

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[1]
Fu, Y.; Dominissini, D.; Rechavi, G.; He, C. Gene expression regulation mediated through reversible m6A RNA methylation. Nat. Rev. Genet., 2014, 15(5), 293-306.
[http://dx.doi.org/10.1038/nrg3724] [PMID: 24662220]
[2]
Meyer, K.D.; Jaffrey, S.R. The dynamic epitranscriptome: N6-methyladenosine and gene expression control. Nat. Rev. Mol. Cell Biol., 2014, 15(5), 313-326.
[http://dx.doi.org/10.1038/nrm3785] [PMID: 24713629]
[3]
Liu, J.; Jia, G. Methylation modifications in eukaryotic messenger RNA. J. Genet. Genomics, 2014, 41(1), 21-33.
[http://dx.doi.org/10.1016/j.jgg.2013.10.002] [PMID: 24480744]
[4]
Liu, L. LITHOPHONE: improving lncRNA methylation site prediction using an ensemble predictor. Front. Genet., 2020.
[5]
Meyer, K.D.; Saletore, Y.; Zumbo, P.; Elemento, O.; Mason, C.E.; Jaffrey, S.R. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell, 2012, 149(7), 1635-1646.
[http://dx.doi.org/10.1016/j.cell.2012.05.003] [PMID: 22608085 ]
[6]
Dominissini, D.; Moshitch-Moshkovitz, S.; Schwartz, S.; Salmon-Divon, M.; Ungar, L.; Osenberg, S.; Cesarkas, K.; Jacob-Hirsch, J.; Amariglio, N.; Kupiec, M.; Sorek, R.; Rechavi, G. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature, 2012, 485(7397), 201-206.
[http://dx.doi.org/10.1038/nature11112] [PMID: 22575960]
[7]
Alarcón, C.R.; Lee, H.; Goodarzi, H.; Halberg, N.; Tavazoie, S.F.N. 6-methyladenosine marks primary microRNAs for processing. Nature, 2015, 519(7544), 482-485.
[http://dx.doi.org/10.1038/nature14281] [PMID: 25799998]
[8]
Liu, N.; Dai, Q.; Zheng, G.; He, C.; Parisien, M.; Pan, T.N. (6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature, 2015, 518(7540), 560-564.
[http://dx.doi.org/10.1038/nature14234] [PMID: 25719671]
[9]
Liu, J.; Yue, Y.; Han, D.; Wang, X.; Fu, Y.; Zhang, L.; Jia, G.; Yu, M.; Lu, Z.; Deng, X.; Dai, Q.; Chen, W.; He, C.A. METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol., 2014, 10(2), 93-95.
[http://dx.doi.org/10.1038/nchembio.1432] [PMID: 24316715]
[10]
Ke, S.; Pandya-Jones, A.; Saito, Y.; Fak, J.J.; Vågbø, C.B.; Geula, S.; Hanna, J.H.; Black, D.L.; Darnell, J.E., Jr; Darnell, R.B. m6A mRNA modifications are deposited in nascent pre-mRNA and are not required for splicing but do specify cytoplasmic turnover. Genes Dev., 2017, 31(10), 990-1006.
[http://dx.doi.org/10.1101/gad.301036.117] [PMID: 28637692]
[11]
Roost, C.; Lynch, S.R.; Batista, P.J.; Qu, K.; Chang, H.Y.; Kool, E.T. Structure and thermodynamics of N6-methyladenosine in RNA: a spring-loaded base modification. J. Am. Chem. Soc., 2015, 137(5), 2107-2115.
[http://dx.doi.org/10.1021/ja513080v] [PMID: 25611135]
[12]
Wang, X.; Lu, Z.; Gomez, A.; Hon, G.C.; Yue, Y.; Han, D.; Fu, Y.; Parisien, M.; Dai, Q.; Jia, G.; Ren, B.; Pan, T.; He, C.N. 6-methyladenosine-dependent regulation of messenger RNA stability. Nature, 2014, 505(7481), 117-120.
[http://dx.doi.org/10.1038/nature12730] [PMID: 24284625]
[13]
Xue, H. Prediction of RNA methylation status from gene expression data using classification and regression methods. Evol. Bioinform. Online, 2020.
[14]
Chen, T.; Hao, Y.J.; Zhang, Y.; Li, M.M.; Wang, M.; Han, W.; Wu, Y.; Lv, Y.; Hao, J.; Wang, L.; Li, A.; Yang, Y.; Jin, K.X.; Zhao, X.; Li, Y.; Ping, X.L.; Lai, W.Y.; Wu, L.G.; Jiang, G.; Wang, H.L.; Sang, L.; Wang, X.J.; Yang, Y.G.; Zhou, Q. m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency. Cell Stem Cell, 2015, 16(3), 289-301.
[http://dx.doi.org/10.1016/j.stem.2015.01.016] [PMID: 25683224]
[15]
Geula, S.; Moshitch-Moshkovitz, S.; Dominissini, D.; Mansour, A.A.; Kol, N.; Salmon-Divon, M.; Hershkovitz, V.; Peer, E.; Mor, N.; Manor, Y.S.; Ben-Haim, M.S.; Eyal, E.; Yunger, S.; Pinto, Y.; Jaitin, D.A.; Viukov, S.; Rais, Y.; Krupalnik, V.; Chomsky, E.; Zerbib, M.; Maza, I.; Rechavi, Y.; Massarwa, R.; Hanna, S.; Amit, I.; Levanon, E.Y.; Amariglio, N.; Stern-Ginossar, N.; Novershtern, N.; Rechavi, G.; Hanna, J.H. Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science, 2015, 347(6225), 1002-1006.
[http://dx.doi.org/10.1126/science.1261417] [PMID: 25569111]
[16]
Fustin, J.M.; Doi, M.; Yamaguchi, Y.; Hida, H.; Nishimura, S.; Yoshida, M.; Isagawa, T.; Morioka, M.S.; Kakeya, H.; Manabe, I.; Okamura, H. RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell, 2013, 155(4), 793-806.
[http://dx.doi.org/10.1016/j.cell.2013.10.026] [PMID: 24209618 ]
[17]
Peng, L.; Yuan, X.; Jiang, B.; Tang, Z.; Li, G.C. LncRNAs: key players and novel insights into cervical cancer. Tumour Biol., 2016, 37(3), 2779-2788.
[http://dx.doi.org/10.1007/s13277-015-4663-9] [PMID: 26715267]
[18]
Martinez, N.M.; Gilbert, W.V. Pre-mRNA modifications and their role in nuclear processing. Quant. Biol., 2018, 6(3), 210-227.
[http://dx.doi.org/10.1007/s40484-018-0147-4] [PMID: 30533247]
[19]
Meng, J.; Cui, X.; Rao, M.K.; Chen, Y.; Huang, Y. Exome-based analysis for RNA epigenome sequencing data. Bioinformatics, 2013, 29(12), 1565-1567.
[http://dx.doi.org/10.1093/bioinformatics/btt171] [PMID: 23589649]
[20]
Valouev, A.; Johnson, D.S.; Sundquist, A.; Medina, C.; Anton, E.; Batzoglou, S.; Myers, R.M.; Sidow, A. Genome-wide analysis of transcription factor binding sites based on ChIP-Seq data. Nat. Methods, 2008, 5(9), 829-834.
[http://dx.doi.org/10.1038/nmeth.1246] [PMID: 19160518]
[21]
Liu, H.; Wang, H.; Wei, Z.; Zhang, S.; Hua, G.; Zhang, S.W.; Zhang, L.; Gao, S.J.; Meng, J.; Chen, X.; Huang, Y. MeT-DB V2.0: elucidating context-specific functions of N6-methyl-adenosine methyltranscriptome. Nucleic Acids Res., 2018, 46(D1), D281-D287.
[http://dx.doi.org/10.1093/nar/gkx1080] [PMID: 29126312]
[22]
Xuan, J.J.; Sun, W.J.; Lin, P.H.; Zhou, K.R.; Liu, S.; Zheng, L.L.; Qu, L.H.; Yang, J.H. RMBase v2.0: deciphering the map of RNA modifications from epitranscriptome sequencing data. Nucleic Acids Res., 2018, 46(D1), D327-D334.
[http://dx.doi.org/10.1093/nar/gkx934] [PMID: 29040692]
[23]
Linder, B.; Grozhik, A.V.; Olarerin-George, A.O.; Meydan, C.; Mason, C.E.; Jaffrey, S.R. Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. Nat. Methods, 2015, 12(8), 767-772.
[http://dx.doi.org/10.1038/nmeth.3453] [PMID: 26121403]
[24]
Chen, W.; Feng, P.; Ding, H.; Lin, H.; Chou, K.C. iRNA-Methyl: Identifying N(6)-methyladenosine sites using pseudo nucleotide composition. Anal. Biochem., 2015, 490, 26-33.
[http://dx.doi.org/10.1016/j.ab.2015.08.021] [PMID: 26314792 ]
[25]
Zhou, Y.; Zeng, P.; Li, Y.H.; Zhang, Z.; Cui, Q. SRAMP: prediction of mammalian N6-methyladenosine (m6A) sites based on sequence-derived features. Nucleic Acids Res., 2016, 44(10)e91
[http://dx.doi.org/10.1093/nar/gkw104] [PMID: 26896799]
[26]
Chen, W.; Tang, H.; Lin, H. MethyRNA: a web server for identification of N6-methyladenosine sites. J. Biomol. Struct. Dyn., 2017, 35(3), 683-687.
[http://dx.doi.org/10.1080/07391102.2016.1157761] [PMID: 26912125]
[27]
Liu, Z.; Xiao, X.; Yu, D.J.; Jia, J.; Qiu, W.R.; Chou, K.C. pRNAm-PC: Predicting N(6)-methyladenosine sites in RNA sequences via physical-chemical properties. Anal. Biochem., 2016, 497, 60-67.
[http://dx.doi.org/10.1016/j.ab.2015.12.017] [PMID: 26748145]
[28]
Chen, W.; Xing, P.; Zou, Q. Detecting N6-methyladenosine sites from RNA transcriptomes using ensemble Support Vector Machines. Sci. Rep., 2017, 7, 40242.
[http://dx.doi.org/10.1038/srep40242] [PMID: 28079126]
[29]
Huang, Y.; He, N.; Chen, Y.; Chen, Z.; Li, L. BERMP: a cross-species classifier for predicting m6A sites by integrating a deep learning algorithm and a random forest approach. Int. J. Biol. Sci., 2018, 14(12), 1669-1677.
[http://dx.doi.org/10.7150/ijbs.27819] [PMID: 30416381]
[30]
Zou, Q.P.X.; Leyi, W.; Bin, L. Gene2vec: gene subsequence embedding for prediction of mammalian N6-methyladenosine sites from mRNA. RNA, 2018, 25(2), 205-218.
[http://dx.doi.org/10.1261/rna.069112.118]
[31]
Zhang, S.Y.; Zhang, S.W.; Fan, X.N.; Meng, J.; Chen, Y.; Gao, S.J.; Huang, Y. Global analysis of N6-methyladenosine functions and its disease association using deep learning and network-based methods. PLOS Comput. Biol., 2019, 15(1)e1006663
[http://dx.doi.org/10.1371/journal.pcbi.1006663] [PMID: 30601803]
[32]
Xiang, S.; Yan, Z.; Liu, K.; Zhang, Y.; Sun, Z. AthMethPre: a web server for the prediction and query of mRNA m6A sites in Arabidopsis thaliana. Mol. Biosyst., 2016, 12(11), 3333-3337.
[http://dx.doi.org/10.1039/C6MB00536E] [PMID: 27550167]
[33]
Li, G.Q. TargetM6A: identifying N6-methyladenosine sites from RNA sequences via position-specific nucleotide propensities and a support vector machine. IEEE Trans Nanobioscience, 2016, PP(99), 1-1.
[http://dx.doi.org/10.1109/TNB.2016.2599115]
[34]
Feng, P.; Ding, H.; Chen, W.; Lin, H. Identifying RNA 5-methylcytosine sites via pseudo nucleotide compositions. Mol. Biosyst., 2016, 12(11), 3307-3311.
[http://dx.doi.org/10.1039/C6MB00471G] [PMID: 27531244]
[35]
Chen, W.; Feng, P.; Tang, H.; Ding, H.; Lin, H. Identifying 2′-O-methylationation sites by integrating nucleotide chemical properties and nucleotide compositions. Genomics, 2016, 107(6), 255-258.
[http://dx.doi.org/10.1016/j.ygeno.2016.05.003] [PMID: 27191866]
[36]
Chen, W. Identification and analysis of the N6-methyladenosine in the Saccharomyces cerevisiae transcriptome. Sci. Rep., 2015, 13859, 5.
[http://dx.doi.org/10.1038/srep13859]
[37]
Zhao, Z.; Peng, H.; Lan, C.; Zheng, Y.; Fang, L.; Li, J. Imbalance learning for the prediction of N6-Methylation sites in mRNAs. BMC Genomics, 2018, 19(1), 574.
[http://dx.doi.org/10.1186/s12864-018-4928-y] [PMID: 30068294]
[38]
Qiu, W.R.; Jiang, S.Y.; Sun, B.Q.; Xiao, X.; Cheng, X.; Chou, K.C. iRNA-2methyl: identify RNA 2′-O-methylation sites by incorporating sequence-coupled effects into general PseKNC and ensemble classifier. Med. Chem., 2017, 13(8), 734-743.
[http://dx.doi.org/10.2174/1573406413666170623082245] [PMID: 28641529]
[39]
Song, B.; Tang, Y.; Wei, Z.; Liu, G.; Su, J.; Meng, J.; Chen, K. PIANO: a web server for pseudouridine site (Ψ) identification and functional annotation. Front. Genet., 2020, 11, 88.
[40]
Zhang, Q. WHISTLE: a high-accuracy map of the human N6- methyladenosine (m6A) epitranscriptome predicted using a machine learning approach. 2019, Nucleic Acids Res., 47(7), e41.
[http://dx.doi.org/10.1093/nar/gkz074]
[41]
Vu, L.P.; Pickering, B.F.; Cheng, Y.; Zaccara, S.; Nguyen, D.; Minuesa, G.; Chou, T.; Chow, A.; Saletore, Y.; MacKay, M.; Schulman, J.; Famulare, C.; Patel, M.; Klimek, V.M.; Garrett-Bakelman, F.E.; Melnick, A.; Carroll, M.; Mason, C.E.; Jaffrey, S.R.; Kharas, M.G. The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat. Med., 2017, 23(11), 1369-1376.
[http://dx.doi.org/10.1038/nm.4416] [PMID: 28920958]
[42]
Ke, S.; Alemu, E.A.; Mertens, C.; Gantman, E.C.; Fak, J.J.; Mele, A.; Haripal, B.; Zucker-Scharff, I.; Moore, M.J.; Park, C.Y.; Vågbø, C.B.; Kusśnierczyk, A.; Klungland, A.; Darnell, J.E., Jr; Darnell, R.B. A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation. Genes Dev., 2015, 29(19), 2037-2053.
[http://dx.doi.org/10.1101/gad.269415.115] [PMID: 26404942]
[43]
Gruber, A.R.; Bernhart, S.H.; Lorenz, R. RNA bioinformatics; Springer, 2015, pp. 307-326.
[http://dx.doi.org/10.1007/978-1-4939-2291-8_19]
[44]
Liu, B. BioSeq-Analysis: a platform for DNA, RNA and protein sequence analysis based on machine learning approaches. Brief. Bioinform., 2017, 20(4), 1280-1294.
[PMID: 29272359]
[45]
Wei, L.; Xing, P.; Su, R.; Shi, G.; Ma, Z.S.; Zou, Q. CPPred-RF: a sequence-based predictor for identifying cell-penetrating peptides and their uptake efficiency. J. Proteome Res., 2017, 16(5), 2044-2053.
[http://dx.doi.org/10.1021/acs.jproteome.7b00019] [PMID: 28436664]
[46]
Song, J. iProt-Sub: a comprehensive tool for accurately mapping and predicting protease-specific substrates and cleavage sites. Brief. Bioinform., 2019, 20(2), 638-658.
[http://dx.doi.org/10.1093/bib/bby028]
[47]
Jia, C.Z.; Zhang, J.J.; Gu, W.Z. RNA-MethylPred: A high-accuracy predictor to identify N6-methyladenosine in RNA. Anal. Biochem., 2016, 510, 72-75.
[http://dx.doi.org/10.1016/j.ab.2016.06.012] [PMID: 27338301]
[48]
Cha, S.; Yu, H.; Park, A.Y.; Oh, S.A.; Kim, J.Y. The obesity-risk variant of FTO is inversely related with the So-Eum constitutional type: genome-wide association and replication analyses. BMC Complement. Altern. Med., 2015, 15(1), 120.
[http://dx.doi.org/10.1186/s12906-015-0609-4] [PMID: 25888059]

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