{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T14:09:10Z","timestamp":1761919750463},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: High-throughput ChIP-seq studies typically identify thousands of peaks for a single transcription factor (TF). It is common for traditional motif discovery tools to predict motifs that are statistically significant against a na\u00efve background distribution but are of questionable biological relevance.<\/jats:p>\n               <jats:p>Results: We describe a simple yet effective algorithm for discovering differential motifs between two sequence datasets that is effective in eliminating systematic biases and scalable to large datasets. Tested on 207 ENCODE ChIP-seq datasets, our method identifies correct motifs in 78% of the datasets with known motifs, demonstrating improvement in both accuracy and efficiency compared with DREME, another state-of-art discriminative motif discovery tool. More interestingly, on the remaining more challenging datasets, we identify common technical or biological factors that compromise the motif search results and use advanced features of our tool to control for these factors. We also present case studies demonstrating the ability of our method to detect single base pair differences in DNA specificity of two similar TFs. Lastly, we demonstrate discovery of key TF motifs involved in tissue specification by examination of high-throughput DNase accessibility data.<\/jats:p>\n               <jats:p>Availability: The motifRG package is publically available via the bioconductor repository.<\/jats:p>\n               <jats:p>Contact: \u00a0yzizhen@fhcrc.org<\/jats:p>\n               <jats:p>Supplementary information:\u2003Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btt615","type":"journal-article","created":{"date-parts":[[2013,10,27]],"date-time":"2013-10-27T00:19:50Z","timestamp":1382833190000},"page":"775-783","source":"Crossref","is-referenced-by-count":39,"title":["Discriminative motif analysis of high-throughput dataset"],"prefix":"10.1093","volume":"30","author":[{"given":"Zizhen","family":"Yao","sequence":"first","affiliation":[{"name":"1 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 2Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, 98105, USA, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 4Department of Pediatrics, School of Medicine, 5Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, 98105, USA, 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 7Department of Computer Science and Engineering, 8Department of Genome Sciences, University of Washington, Seattle, Washington, 98105, USA and 9Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle L.","family":"MacQuarrie","sequence":"additional","affiliation":[{"name":"1 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 2Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, 98105, USA, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 4Department of Pediatrics, School of Medicine, 5Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, 98105, USA, 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 7Department of Computer Science and Engineering, 8Department of Genome Sciences, University of Washington, Seattle, Washington, 98105, USA and 9Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA"},{"name":"1 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 2Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, 98105, USA, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 4Department of Pediatrics, School of Medicine, 5Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, 98105, USA, 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 7Department of Computer Science and Engineering, 8Department of Genome Sciences, University of Washington, Seattle, Washington, 98105, USA and 9Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abraham P.","family":"Fong","sequence":"additional","affiliation":[{"name":"1 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 2Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, 98105, USA, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 4Department of Pediatrics, School of Medicine, 5Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, 98105, USA, 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 7Department of Computer Science and Engineering, 8Department of Genome Sciences, University of Washington, Seattle, Washington, 98105, USA and 9Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA"},{"name":"1 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 2Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, 98105, USA, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 4Department of Pediatrics, School of Medicine, 5Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, 98105, USA, 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 7Department of Computer Science and Engineering, 8Department of Genome Sciences, University of Washington, Seattle, Washington, 98105, USA and 9Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen J.","family":"Tapscott","sequence":"additional","affiliation":[{"name":"1 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 2Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, 98105, USA, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 4Department of Pediatrics, School of Medicine, 5Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, 98105, USA, 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 7Department of Computer Science and Engineering, 8Department of Genome Sciences, University of Washington, Seattle, Washington, 98105, USA and 9Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA"},{"name":"1 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 2Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, 98105, USA, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 4Department of Pediatrics, School of Medicine, 5Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, 98105, USA, 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 7Department of Computer Science and Engineering, 8Department of Genome Sciences, University of Washington, Seattle, Washington, 98105, USA and 9Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA"},{"name":"1 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 2Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, 98105, USA, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 4Department of Pediatrics, School of Medicine, 5Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, 98105, USA, 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 7Department of Computer Science and Engineering, 8Department of Genome Sciences, University of Washington, Seattle, Washington, 98105, USA and 9Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter L.","family":"Ruzzo","sequence":"additional","affiliation":[{"name":"1 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 2Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, 98105, USA, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 4Department of Pediatrics, School of Medicine, 5Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, 98105, USA, 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 7Department of Computer Science and Engineering, 8Department of Genome Sciences, University of Washington, Seattle, Washington, 98105, USA and 9Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA"},{"name":"1 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 2Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, 98105, USA, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 4Department of Pediatrics, School of Medicine, 5Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, 98105, USA, 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 7Department of Computer Science and Engineering, 8Department of Genome Sciences, University of Washington, Seattle, Washington, 98105, USA and 9Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA"},{"name":"1 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 2Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, 98105, USA, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 4Department of Pediatrics, School of Medicine, 5Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, 98105, USA, 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 7Department of Computer Science and Engineering, 8Department of Genome Sciences, University of Washington, Seattle, Washington, 98105, USA and 9Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert C.","family":"Gentleman","sequence":"additional","affiliation":[{"name":"1 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 2Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, 98105, USA, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 4Department of Pediatrics, School of Medicine, 5Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, 98105, USA, 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 7Department of Computer Science and Engineering, 8Department of Genome Sciences, University of Washington, Seattle, Washington, 98105, USA and 9Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,10,25]]},"reference":[{"key":"2023012710442659500_btt615-B1","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1093\/bioinformatics\/btr261","article-title":"DREME: motif discovery in transcription factor ChIP-seq data","volume":"27","author":"Bailey","year":"2011","journal-title":"Bioinformatics"},{"key":"2023012710442659500_btt615-B2","first-page":"21","article-title":"The value of prior knowledge in discovering motifs with MEME","volume":"3","author":"Bailey","year":"1995","journal-title":"Proc. Int. Conf. Intell. Syst. Mol. Biol."},{"key":"2023012710442659500_btt615-B3","doi-asserted-by":"crossref","first-page":"e128","DOI":"10.1093\/nar\/gks433","article-title":"Inferring direct DNA binding from ChIP-seq","volume":"40","author":"Bailey","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2023012710442659500_btt615-B4","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/nprot.2008.195","article-title":"Universal protein-binding microarrays for the comprehensive characterization of the DNA-binding specificities of transcription factors","volume":"4","author":"Berger","year":"2009","journal-title":"Nat. Protoc."},{"key":"2023012710442659500_btt615-B5","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.chemolab.2005.05.004","article-title":"Receiver operating characteristics curves and related decision measures: a tutorial","volume":"80","author":"Brown","year":"2006","journal-title":"Chemometr. Intell. Lab. Syst."},{"key":"2023012710442659500_btt615-B6","doi-asserted-by":"crossref","first-page":"D102","DOI":"10.1093\/nar\/gkm955","article-title":"JASPAR, the open access database of transcription factor-binding profiles: new content and tools in the 2008 update","volume":"36","author":"Bryne","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"2023012710442659500_btt615-B7","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/84792","article-title":"Regulatory element detection using correlation with expression","volume":"27","author":"Bussemaker","year":"2001","journal-title":"Nat. Genet."},{"key":"2023012710442659500_btt615-B8","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.devcel.2010.02.014","article-title":"Genome-wide MyoD binding in skeletal muscle cells: a potential for broad cellular reprogramming","volume":"18","author":"Cao","year":"2010","journal-title":"Dev. Cell"},{"key":"2023012710442659500_btt615-B9","doi-asserted-by":"crossref","first-page":"i72","DOI":"10.1093\/bioinformatics\/btm224","article-title":"RankMotif++: a motif-search algorithm that accounts for relative ranks of K-mers in binding transcription factors","volume":"23","author":"Chen","year":"2007","journal-title":"Bioinformatics"},{"key":"2023012710442659500_btt615-B10","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.devcel.2012.01.015","article-title":"Genetic and epigenetic determinants of neurogenesis and myogenesis","volume":"22","author":"Fong","year":"2012","journal-title":"Dev. Cell."},{"key":"2023012710442659500_btt615-B11","doi-asserted-by":"crossref","first-page":"R80","DOI":"10.1186\/gb-2004-5-10-r80","article-title":"Bioconductor: open software development for computational biology and bioinformatics","volume":"5","author":"Gentleman","year":"2004","journal-title":"Genome Biol."},{"key":"2023012710442659500_btt615-B12","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1093\/bioinformatics\/15.7.563","article-title":"Identifying DNA and protein patterns with statistically significant alignments of multiple sequences","volume":"15","author":"Hertz","year":"1999","journal-title":"Bioinformatics"},{"key":"2023012710442659500_btt615-B13","doi-asserted-by":"crossref","DOI":"10.1002\/0471722146","volume-title":"Applied logistic regression Wiley-Interscience","author":"Hosmer","year":"2000"},{"key":"2023012710442659500_btt615-B14","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/ng.759","article-title":"Chromatin accessibility pre-determines glucocorticoid receptor binding patterns","volume":"43","author":"John","year":"2011","journal-title":"Nat. Genet."},{"key":"2023012710442659500_btt615-B15","doi-asserted-by":"crossref","first-page":"4122","DOI":"10.4049\/jimmunol.153.9.4122","article-title":"The role of NF-Y and IRF-2 in the regulation of human IL-4 gene expression","volume":"153","author":"Li-Weber","year":"1994","journal-title":"J. Immunol."},{"key":"2023012710442659500_btt615-B16","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nature11212","article-title":"An expansive human regulatory lexicon encoded in transcription factor footprints","volume":"489","author":"Neph","year":"2012","journal-title":"Nature"},{"key":"2023012710442659500_btt615-B17","doi-asserted-by":"crossref","first-page":"D77","DOI":"10.1093\/nar\/gkn660","article-title":"UniPROBE: an online database of protein binding microarray data on protein-DNA interactions","volume":"37","author":"Newburger","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2023012710442659500_btt615-B18","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.cell.2008.01.011","article-title":"Cohesins functionally associate with CTCF on mammalian chromosome arms","volume":"132","author":"Parelho","year":"2008","journal-title":"Cell"},{"key":"2023012710442659500_btt615-B19","doi-asserted-by":"crossref","first-page":"e11881","DOI":"10.1371\/journal.pone.0011881","article-title":"PeakRegressor identifies composite sequence motifs responsible for STAT1 binding sites and their potential rSNPs","volume":"5","author":"Pessiot","year":"2010","journal-title":"PLoS One"},{"key":"2023012710442659500_btt615-B20","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1186\/1471-2105-8-385","article-title":"Discriminative motif discovery in DNA and protein sequences using the DEME algorithm","volume":"8","author":"Redhead","year":"2007","journal-title":"BMC Bioinformatics"},{"key":"2023012710442659500_btt615-B21","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1101\/gad.1890410","article-title":"Precise temporal control of the eye regulatory gene Pax6 via enhancer-binding site affinity","volume":"24","author":"Rowan","year":"2010","journal-title":"Genes Dev."},{"key":"2023012710442659500_btt615-B22","doi-asserted-by":"crossref","first-page":"e454","DOI":"10.1093\/bioinformatics\/btl227","article-title":"On counting position weight matrix matches in a sequence, with application to discriminative motif finding","volume":"22","author":"Sinha","year":"2006","journal-title":"Bioinformatics"},{"key":"2023012710442659500_btt615-B23","doi-asserted-by":"crossref","first-page":"6275","DOI":"10.1073\/pnas.0508169103","article-title":"DNA motifs in human and mouse proximal promoters predict tissue-specific expression","volume":"103","author":"Smith","year":"2006","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012710442659500_btt615-B24","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0968-0004(98)01187-6","article-title":"Specificity, free energy and information content in protein-DNA interactions","volume":"23","author":"Stormo","year":"1998","journal-title":"Trends Biochem. Sci."},{"key":"2023012710442659500_btt615-B25","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1093\/bioinformatics\/btr257","article-title":"Improved similarity scores for comparing motifs","volume":"27","author":"Tanaka","year":"2011","journal-title":"Bioinformatics"},{"key":"2023012710442659500_btt615-B26","article-title":"R: A language and environment for statistical computing","author":"R Development Core Team","year":"2010","journal-title":"R Foundation for Statistical Computing, Vienna, Austria"},{"key":"2023012710442659500_btt615-B27","doi-asserted-by":"crossref","first-page":"e31","DOI":"10.1093\/nar\/gkr1104","article-title":"RSAT peak-motifs: motif analysis in full-size ChIP-seq datasets","volume":"40","author":"Thomas-Chollier","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2023012710442659500_btt615-B28","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/nbt1053","article-title":"Assessing computational tools for the discovery of transcription factor binding sites","volume":"23","author":"Tompa","year":"2005","journal-title":"Nat. Biotechnol."},{"key":"2023012710442659500_btt615-B29","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1111\/j.1365-2567.2010.03381.x","article-title":"Interplay of transcription factors in T-cell differentiation and function: the role of Runx","volume":"132","author":"Wong","year":"2011","journal-title":"Immunology"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/30\/6\/775\/48921639\/bioinformatics_30_6_775.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/30\/6\/775\/48921639\/bioinformatics_30_6_775.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T11:06:06Z","timestamp":1674817566000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/30\/6\/775\/286088"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,10,25]]},"references-count":29,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2014,3,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btt615","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2014,3,15]]},"published":{"date-parts":[[2013,10,25]]}}}