{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T03:16:44Z","timestamp":1780111004729,"version":"3.54.0"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Bioinformatics"],"published-print":{"date-parts":[[2007,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Despite the diversity of motif representations and search algorithms, the<jats:italic>de novo<\/jats:italic>computational identification of transcription factor binding sites remains constrained by the limited accuracy of existing algorithms and the need for user-specified input parameters that describe the motif being sought.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We present a novel ensemble learning method, SCOPE, that is based on the assumption that transcription factor binding sites belong to one of three broad classes of motifs: non-degenerate, degenerate and gapped motifs. SCOPE employs a unified scoring metric to combine the results from three motif finding algorithms each aimed at the discovery of one of these classes of motifs. We found that SCOPE's performance on 78 experimentally characterized regulons from four species was a substantial and statistically significant improvement over that of its component algorithms. SCOPE outperformed a broad range of existing motif discovery algorithms on the same dataset by a statistically significant margin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>SCOPE demonstrates that combining multiple, focused motif discovery algorithms can provide a significant gain in performance. By building on components that efficiently search for motifs without user-defined parameters, SCOPE requires as input only a set of upstream sequences and a species designation, making it a practical choice for non-expert users. A user-friendly web interface, Java source code and executables are available at<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/genie.dartmouth.edu\/scope\" ext-link-type=\"uri\">http:\/\/genie.dartmouth.edu\/scope<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1471-2105-8-249","type":"journal-article","created":{"date-parts":[[2007,7,12]],"date-time":"2007-07-12T18:13:36Z","timestamp":1184264016000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["A novel ensemble learning method for de novo computational identification of DNA binding sites"],"prefix":"10.1186","volume":"8","author":[{"given":"Arijit","family":"Chakravarty","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M","family":"Carlson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radhika S","family":"Khetani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H","family":"Gross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2007,7,12]]},"reference":[{"key":"1621_CR1","doi-asserted-by":"publisher","first-page":"e36","DOI":"10.1371\/journal.pcbi.0020036","volume":"2","author":"KD MacIsaac","year":"2006","unstructured":"MacIsaac KD, Fraenkel E: Practical strategies for discovering regulatory DNA sequence motifs. PLoS Comput Biol. 2006, 2: e36-","journal-title":"PLoS Comput Biol"},{"key":"1621_CR2","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1038\/nrg1315","volume":"5","author":"WW Wasserman","year":"2004","unstructured":"Wasserman WW, Sandelin A: Applied bioinformatics for the identification of regulatory elements. Nat Rev Genet. 2004, 5: 276-287.","journal-title":"Nat Rev Genet"},{"key":"1621_CR3","doi-asserted-by":"publisher","first-page":"3585","DOI":"10.1093\/nar\/gkl372","volume":"34","author":"D GuhaThakurta","year":"2006","unstructured":"GuhaThakurta D: Computational identification of transcriptional regulatory elements in DNA sequence. Nucleic Acids Res. 2006, 34: 3585-3598.","journal-title":"Nucleic Acids Res"},{"key":"1621_CR4","doi-asserted-by":"publisher","first-page":"4899","DOI":"10.1093\/nar\/gki791","volume":"33","author":"J Hu","year":"2005","unstructured":"Hu J, Li B, Kihara D: Limitations and potentials of current motif discovery algorithms. Nucleic Acids Res. 2005, 33: 4899-4913.","journal-title":"Nucleic Acids Res"},{"key":"1621_CR5","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/nbt1053","volume":"23","author":"M Tompa","year":"2005","unstructured":"Tompa M, Li N, Bailey TL, Church GM, De Moor B, Eskin E, Favorov AV, Frith MC, Fu Y, Kent WJ, Makeev VJ, Mironov AA, Noble WS, Pavesi G, Pesole G, R\u00e9gnier M, Simonis N, Sinha S, Thijs G, van Helden J, Vandenbogaert M, Weng Z, Workman C, Ye C, Zhu Z: Assessing computational tools for the discovery of transcription factor binding sites. Nat Biotechnol. 2005, 23: 137-144.","journal-title":"Nat Biotechnol"},{"key":"1621_CR6","first-page":"214","volume-title":"Third IEEE Symposium on Bioinformatics and Bioengineering","author":"S Sinha","year":"2003","unstructured":"Sinha S, Tompa M: Performance comparison of algorithms for finding transcription factor binding sites. Third IEEE Symposium on Bioinformatics and Bioengineering. 2003, Los Alamitos: IEEE Press, 214-220."},{"issue":"Suppl 2","key":"1621_CR7","doi-asserted-by":"publisher","first-page":"II206","DOI":"10.1093\/bioinformatics\/btg1079","volume":"19","author":"D Shinozaki","year":"2003","unstructured":"Shinozaki D, Akutsu T, Maruyama O: Finding optimal degenerate patterns in DNA sequences. Bioinformatics. 2003, 19 (Suppl 2): II206-II214.","journal-title":"Bioinformatics"},{"key":"1621_CR8","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/nature02800","volume":"431","author":"CT Harbison","year":"2004","unstructured":"Harbison CT, Gordon DB, Lee TI, Rinaldi NJ, Macisaac KD, Danford TW, Hannett NM, Tagne JB, Reynolds DB, Yoo J, Jennings EG, Zeitlinger J, Pokholok DK, Kellis M, Rolfe PA, Takusagawa KT, Lander ES, Gifford DK, Faenkel E, Young RA: Transcriptional regulatory code of a eukaryotic genome. Nature. 2004, 431: 99-104.","journal-title":"Nature"},{"key":"1621_CR9","volume-title":"Machine learning","author":"T Mitchell","year":"1997","unstructured":"Mitchell T: Machine learning. 1997, McGraw Hill"},{"key":"1621_CR10","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1089\/cmb.2006.13.686","volume":"13","author":"JM Carlson","year":"2006","unstructured":"Carlson JM, Chakravarty A, Gross RH: BEAM: a beam search algorithm for the identification of cis-regulatory elements in groups of genes. J Comput Biol. 2006, 13: 686-701.","journal-title":"J Comput Biol"},{"key":"1621_CR11","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1186\/1471-2105-7-254","volume":"7","author":"JM Carlson","year":"2006","unstructured":"Carlson JM, Chakravarty A, Khetani RS, Gross RH: Bounded search for de novo identification of degenerate cis-regulatory elements. BMC Bioinformatics. 2006, 7: 254-","journal-title":"BMC Bioinformatics"},{"key":"1621_CR12","volume-title":"Bioinformatics","author":"A Chakravarty","year":"2007","unstructured":"Chakravarty A, Carlson JM, Khetani RS, DeZiel CE, Gross RH: SPACER: Identification of cis-regulatory elements with non-contiguous critical residues. Bioinformatics. 2007"},{"key":"1621_CR13","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1089\/10665270252935430","volume":"9","author":"J Buhler","year":"2002","unstructured":"Buhler J, Tompa M: Finding motifs using random projections. J Comput Biol. 2002, 9: 225-242.","journal-title":"J Comput Biol"},{"key":"1621_CR14","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1006\/jmbi.1998.1947","volume":"281","author":"J van Helden","year":"1998","unstructured":"van Helden J, Andre B, Collado-Vides J: Extracting regulatory sites from the upstream region of yeast genes by computational analysis of oligonucleotide frequencies. J Mol Biol. 1998, 281: 827-842.","journal-title":"J Mol Biol"},{"key":"1621_CR15","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1093\/bioinformatics\/15.7.607","volume":"15","author":"J Zhu","year":"1999","unstructured":"Zhu J, Zhang MQ: SCPD: a promoter database of the yeast Saccharomyces cerevisiae. Bioinformatics. 1999, 15: 607-611.","journal-title":"Bioinformatics"},{"key":"1621_CR16","first-page":"127","volume-title":"Pac Symp Biocomput","author":"X Liu","year":"2001","unstructured":"Liu X, Brutlag DL, Liu JS: BioProspector: discovering conserved DNA motifs in upstream regulatory regions of co-expressed genes. Pac Symp Biocomput. 2001, 127-138."},{"key":"1621_CR17","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1093\/bioinformatics\/16.1.16","volume":"16","author":"GD Stormo","year":"2000","unstructured":"Stormo GD: DNA binding sites: representation and discovery. Bioinformatics. 2000, 16: 16-23.","journal-title":"Bioinformatics"},{"key":"1621_CR18","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1109\/4235.585893","volume":"1","author":"D Wolpert","year":"1997","unstructured":"Wolpert D, Macready W: No free lunch theorems for optimization. IEEE Transactions on Evolutionary Computation. 1997, 1: 67-82.","journal-title":"IEEE Transactions on Evolutionary Computation"},{"key":"1621_CR19","first-page":"SFI-TR-05-010","volume-title":"No free lunch theorems for search","author":"D Wolpert","year":"1995","unstructured":"Wolpert D, Macready W: No free lunch theorems for search. 1995, Santa Fe: Santa Fe Institute, SFI-TR-05-010-"},{"key":"1621_CR20","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1023\/A:1021251113462","volume":"115","author":"YC Ho","year":"2002","unstructured":"Ho YC, Pepyne DL: Simple Explanation of the No-Free-Lunch Theorem and Its Implications. Journal of Optimization Theory and Applications. 2002, 115: 549-570.","journal-title":"Journal of Optimization Theory and Applications"},{"key":"1621_CR21","doi-asserted-by":"publisher","first-page":"11168","DOI":"10.1073\/pnas.91.23.11168","volume":"91","author":"Y Choo","year":"1994","unstructured":"Choo Y, Klug A: Selection of DNA binding sites for zinc fingers using rationally randomized DNA reveals coded interactions. Proc Natl Acad Sci USA. 1994, 91: 11168-11172.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1621_CR22","volume-title":"Data Mining","author":"IH Witten","year":"2000","unstructured":"Witten IH, Frank E: Data Mining. 2000, San Diego: Academic Press"},{"key":"1621_CR23","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-21606-5","volume-title":"The Elements of Statistical Learning","author":"T Hastie","year":"2001","unstructured":"Hastie T, Tibshirani R, Friedman JH: The Elements of Statistical Learning. 2001, New York, NY: Springer"},{"key":"1621_CR24","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/1471-2105-4-65","volume":"4","author":"AG Nazina","year":"2003","unstructured":"Nazina AG, Papatsenko DA: Statistical extraction of Drosophila cis-regulatory modules using exhaustive assessment of local word frequency. BMC Bioinformatics. 2003, 4: 65-","journal-title":"BMC Bioinformatics"},{"key":"1621_CR25","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1073\/pnas.231608898","volume":"99","author":"BP Berman","year":"2002","unstructured":"Berman BP, Nibu Y, Pfeiffer BD, Tomancak P, Celniker SE, Levine M, Rubin GM, Eisen MB: Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome. Proc Natl Acad Sci USA. 2002, 99: 757-762.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1621_CR26","doi-asserted-by":"publisher","first-page":"R61","DOI":"10.1186\/gb-2004-5-9-r61","volume":"5","author":"BP Berman","year":"2004","unstructured":"Berman BP, Pfeiffer BD, Laverty TR, Salzberg SL, Rubin GM, Eisen MB, Celniker SE: Computational identification of developmental enhancers: conservation and function of transcription factor binding-site clusters in Drosophila melanogaster and Drosophila pseudoobscura. Genome Biol. 2004, 5: R61-","journal-title":"Genome Biol"},{"key":"1621_CR27","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1101\/gr.228902","volume":"12","author":"MS Halfon","year":"2002","unstructured":"Halfon MS, Grad Y, Church GM, Michelson AM: Computation-based discovery of related transcriptional regulatory modules and motifs using an experimentally validated combinatorial model. Genome Res. 2002, 12: 1019-1028.","journal-title":"Genome Res"},{"key":"1621_CR28","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/1471-2105-3-30","volume":"3","author":"N Rajewsky","year":"2002","unstructured":"Rajewsky N, Vergassola M, Gaul U, Siggia ED: Computational detection of genomic cis-regulatory modules applied to body patterning in the early Drosophila embryo. BMC Bioinformatics. 2002, 3: 30-","journal-title":"BMC Bioinformatics"},{"key":"1621_CR29","first-page":"269","volume":"8","author":"PA Pevzner","year":"2000","unstructured":"Pevzner PA, Sze SH: Combinatorial approaches to finding subtle signals in DNA sequences. Proc Int Conf Intell Syst Mol Biol. 2000, 8: 269-278.","journal-title":"Proc Int Conf Intell Syst Mol Biol"},{"key":"1621_CR30","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1146\/annurev.biochem.72.121801.161520","volume":"72","author":"ST Smale","year":"2003","unstructured":"Smale ST, Kadonaga JT: The RNA polymerase II core promoter. Annu Rev Biochem. 2003, 72: 449-479.","journal-title":"Annu Rev Biochem"},{"key":"1621_CR31","volume-title":"Numerical recipes in C","author":"WH Press","year":"1992","unstructured":"Press WH, Teukolsky SA, Vetterling WT, Flannery BP: Numerical recipes in C. 1992, New York: Cambridge University Press"},{"key":"1621_CR32","doi-asserted-by":"publisher","first-page":"1562","DOI":"10.1101\/gr.1953904","volume":"14","author":"PC FitzGerald","year":"2004","unstructured":"FitzGerald PC, Shlyakhtenko A, Mir AA, Vinson C: Clustering of DNA sequences in human promoters. Genome Res. 2004, 14: 1562-1574.","journal-title":"Genome Res"},{"key":"1621_CR33","doi-asserted-by":"publisher","first-page":"3593","DOI":"10.1093\/nar\/gkg567","volume":"31","author":"J van Helden","year":"2003","unstructured":"van Helden J: Regulatory sequence analysis tools. Nucleic Acids Res. 2003, 31: 3593-3596.","journal-title":"Nucleic Acids Res"},{"key":"1621_CR34","doi-asserted-by":"publisher","first-page":"1808","DOI":"10.1093\/nar\/28.8.1808","volume":"28","author":"J van Helden","year":"2000","unstructured":"van Helden J, Rios AF, Collado-Vides J: Discovering regulatory elements in non-coding sequences by analysis of spaced dyads. Nucleic Acids Res. 2000, 28: 1808-1818.","journal-title":"Nucleic Acids Res"},{"key":"1621_CR35","doi-asserted-by":"publisher","first-page":"3586","DOI":"10.1093\/nar\/gkg618","volume":"31","author":"S Sinha","year":"2003","unstructured":"Sinha S, Tompa M: YMF: A program for discovery of novel transcription factor binding sites by statistical overrepresentation. Nucleic Acids Res. 2003, 31: 3586-3588.","journal-title":"Nucleic Acids Res"},{"key":"1621_CR36","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1038\/nbt1098-939","volume":"16","author":"FP Roth","year":"1998","unstructured":"Roth FP, Hughes JD, Estep PW, Church GM: Finding DNA regulatory motifs within unaligned noncoding sequences clustered by whole-genome mRNA quantitation. Nat Biotechnol. 1998, 16: 939-945.","journal-title":"Nat Biotechnol"},{"key":"1621_CR37","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1093\/bioinformatics\/17.12.1113","volume":"17","author":"G Thijs","year":"2001","unstructured":"Thijs G, Lescot M, Marchal K, Rombauts S, De Moor B, Rouze P, Moreau Y: A higher-order background model improves the detection of promoter regulatory elements by Gibbs sampling. Bioinformatics. 2001, 17: 1113-1122.","journal-title":"Bioinformatics"},{"key":"1621_CR38","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1038\/nbt717","volume":"20","author":"XS Liu","year":"2002","unstructured":"Liu XS, Brutlag DL, Liu JS: An algorithm for finding protein-DNA binding sites with applications to chromatin-immunoprecipitation microarray experiments. Nat Biotechnol. 2002, 20: 835-839.","journal-title":"Nat Biotechnol"},{"key":"1621_CR39","first-page":"51","volume":"21","author":"TL Bailey","year":"1995","unstructured":"Bailey TL, Elkan C: Unsupervised learning of multiple motifs in biopolymers using expectation maximization. Machine learning. 1995, 21: 51-80.","journal-title":"Machine learning"},{"key":"1621_CR40","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1126\/science.1102216","volume":"305","author":"W Ao","year":"2004","unstructured":"Ao W, Gaudet J, Kent WJ, Muttumu S, Mango SE: Environmentally induced foregut remodeling by PHA-4\/FoxA and DAF-12\/NHR. Science. 2004, 305: 1743-1746.","journal-title":"Science"},{"issue":"Suppl 1","key":"1621_CR41","doi-asserted-by":"publisher","first-page":"S354","DOI":"10.1093\/bioinformatics\/18.suppl_1.S354","volume":"18","author":"E Eskin","year":"2002","unstructured":"Eskin E, Pevzner PA: Finding composite regulatory patterns in DNA sequences. Bioinformatics. 2002, 18 (Suppl 1): S354-363.","journal-title":"Bioinformatics"},{"key":"1621_CR42","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1093\/bioinformatics\/15.7.563","volume":"15","author":"GZ Hertz","year":"1999","unstructured":"Hertz GZ, Stormo GD: Identifying DNA and protein patterns with statistically significant alignments of multiple sequences. Bioinformatics. 1999, 15: 563-577.","journal-title":"Bioinformatics"},{"issue":"Suppl 1","key":"1621_CR43","doi-asserted-by":"publisher","first-page":"S207","DOI":"10.1093\/bioinformatics\/17.suppl_1.S207","volume":"17","author":"G Pavesi","year":"2001","unstructured":"Pavesi G, Mauri G, Pesole G: An algorithm for finding signals of unknown length in DNA sequences. Bioinformatics. 2001, 17 (Suppl 1): S207-214.","journal-title":"Bioinformatics"}],"container-title":["BMC Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2105-8-249.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T09:11:10Z","timestamp":1683969070000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbioinformatics.biomedcentral.com\/articles\/10.1186\/1471-2105-8-249"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,7,12]]},"references-count":43,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2007,12]]}},"alternative-id":["1621"],"URL":"https:\/\/doi.org\/10.1186\/1471-2105-8-249","relation":{},"ISSN":["1471-2105"],"issn-type":[{"value":"1471-2105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,7,12]]},"assertion":[{"value":"6 March 2007","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 July 2007","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 July 2007","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"249"}}