{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T22:42:07Z","timestamp":1760222527780,"version":"build-2065373602"},"reference-count":138,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2009,3,24]],"date-time":"2009-03-24T00:00:00Z","timestamp":1237852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Algorithms"],"abstract":"<jats:p>The discovery of gene regulatory elements requires the synergism between computational and experimental techniques in order to reveal the underlying regulatory mechanisms that drive gene expression in response to external cues and signals. Utilizing the large amount of high-throughput experimental data, constantly growing in recent years, researchers have attempted to decipher the patterns which are hidden in the genomic sequences. These patterns, called motifs, are potential binding sites to transcription factors which are hypothesized to be the main regulators of the transcription process. Consequently, precise detection of these elements is required and thus a large number of computational approaches have been developed to support the de novo identification of TFBSs. Even though novel approaches are continuously proposed and almost all have reported some success in yeast and other lower organisms, in higher organisms the problem still remains a challenge. In this paper, we therefore review the recent developments in computational methods for transcription factor binding site prediction. We start with a brief review of the basic approaches for binding site representation and promoter identification, then discuss the techniques to locate physical TFBSs, identify functional binding sites using orthologous information, and infer functional TFBSs within some context defined by additional prior knowledge. Finally, we briefly explore the opportunities for expanding these approaches towards the computational identification of transcriptional regulatory networks.<\/jats:p>","DOI":"10.3390\/a2010582","type":"journal-article","created":{"date-parts":[[2009,3,26]],"date-time":"2009-03-26T13:02:18Z","timestamp":1238072538000},"page":"582-605","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Recent Advances in the Computational Discovery of Transcription Factor Binding Sites"],"prefix":"10.3390","volume":"2","author":[{"given":"Tung T.","family":"Nguyen","sequence":"first","affiliation":[{"name":"BioMaPS Institute for Quantitative Biology, Rutgers University, New Jersey 08854, USA"}]},{"given":"Ioannis P.","family":"Androulakis","sequence":"additional","affiliation":[{"name":"Biomedical Engineering Department, Rutgers University, New Jersey 08854, USA"}]}],"member":"1968","published-online":{"date-parts":[[2009,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/S0022-2836(02)00427-8","article-title":"A revolutionary landscape: the restructuring of biology and its convergence with medicine","volume":"319","author":"Kafatos","year":"2002","journal-title":"J Mol Biol"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1101\/gad.831000","article-title":"Orchestrated response: a symphony of transcription factors for gene control","volume":"14","author":"Lemon","year":"2000","journal-title":"Genes Dev"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/nature01763","article-title":"Transcription regulation and animal diversity","volume":"424","author":"Levine","year":"2003","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4067","DOI":"10.1242\/jcs.00779","article-title":"The eukaryotic genome: a system regulated at different hierarchical levels","volume":"116","author":"Fransz","year":"2003","journal-title":"J Cell Sci"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1096\/fj.02-0955rev","article-title":"Computer modeling of promoter organization as a tool to study transcriptional coregulation","volume":"17","author":"Werner","year":"2003","journal-title":"Faseb J"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/gr.4222606","article-title":"Comprehensive analysis of transcriptional promoter structure and function in 1% of the human genome","volume":"16","author":"Cooper","year":"2006","journal-title":"Genome Res"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev.genom.7.080505.115623","article-title":"Transcriptional regulatory elements in the human genome","volume":"7","author":"Maston","year":"2006","journal-title":"Annu Rev Genomics Hum Genet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1007\/s00018-006-6295-0","article-title":"The gateway to transcription: identifying, characterizing and understanding promoters in the eukaryotic genome","volume":"64","author":"Heintzman","year":"2007","journal-title":"Cell Mol Life Sci"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.ceb.2006.04.002","article-title":"The transcriptional regulatory code of eukaryotic cells--insights from genome-wide analysis of chromatin organization and transcription factor binding","volume":"18","author":"Barrera","year":"2006","journal-title":"Curr Opin Cell Biol"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s10577-006-1027-8","article-title":"Gene regulation and large-scale chromatin organization in the nucleus","volume":"14","author":"Dillon","year":"2006","journal-title":"Chromosome Res"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1002\/jcb.21521","article-title":"Nuclear architecture: Is it important for genome function and can we prove it?","volume":"102","author":"Goetze","year":"2007","journal-title":"J Cell Biochem"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3027","DOI":"10.1101\/gad.1604607","article-title":"Dynamics and interplay of nuclear architecture, genome organization, and gene expression","volume":"21","author":"Schneider","year":"2007","journal-title":"Genes Dev"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1093\/molbev\/msg140","article-title":"The evolution of transcriptional regulation in eukaryotes","volume":"20","author":"Wray","year":"2003","journal-title":"Mol Biol Evol"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.tig.2003.09.014","article-title":"Complex controls: the role of alternative promoters in mammalian genomes","volume":"19","author":"Landry","year":"2003","journal-title":"Trends Genet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1186\/1471-2164-9-349","article-title":"Genome-wide analysis of alternative promoters of human genes using a custom promoter tiling array","volume":"9","author":"Singer","year":"2008","journal-title":"BMC Genomics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1745-6150-1-11","article-title":"A survey of motif discovery methods in an integrated framework","volume":"1","author":"Sandve","year":"2006","journal-title":"Biol Direct"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/gb-2003-5-1-201","article-title":"Computational prediction of transcription-factor binding site locations","volume":"5","author":"Bulyk","year":"2003","journal-title":"Genome Biol"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/nbt1233","article-title":"High-resolution computational models of genome binding events","volume":"24","author":"Qi","year":"2006","journal-title":"Nat Biotechnol"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.1126\/science.290.5500.2306","article-title":"Genome-wide location and function of DNA binding proteins","volume":"290","author":"Ren","year":"2000","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1038\/nbt718","article-title":"High-throughput SELEX SAGE method for quantitative modeling of transcription-factor binding sites","volume":"20","author":"Roulet","year":"2002","journal-title":"Nat Biotechnol"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.bioeng.2007.06.001","article-title":"SELEX--a (r)evolutionary method to generate high-affinity nucleic acid ligands","volume":"24","author":"Stoltenburg","year":"2007","journal-title":"Biomol Eng"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4899","DOI":"10.1093\/nar\/gki791","article-title":"Limitations and potentials of current motif discovery algorithms","volume":"33","author":"Hu","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/1471-2105-8-193","article-title":"Improved benchmarks for computational motif discovery","volume":"8","author":"Sandve","year":"2007","journal-title":"BMC Bioinformatics"},{"key":"ref_24","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":"ref_25","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/1471-2105-9-123","article-title":"Assessment of composite motif discovery methods","volume":"9","author":"Klepper","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S21","DOI":"10.1186\/1471-2105-8-S7-S21","article-title":"A survey of DNA motif finding algorithms","volume":"8","author":"Das","year":"2007","journal-title":"BMC Bioinformatics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"R56","DOI":"10.1186\/gb-2004-5-8-r56","article-title":"Identifying combinatorial regulation of transcription factors and binding motifs","volume":"5","author":"Kato","year":"2004","journal-title":"Genome Biol"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.jbi.2007.02.003","article-title":"A new framework for identifying combinatorial regulation of transcription factors: a case study of the yeast cell cycle","volume":"40","author":"Wang","year":"2007","journal-title":"J Biomed Inform"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1089\/cmb.1998.5.279","article-title":"Approaches to the automatic discovery of patterns in biosequences","volume":"5","author":"Brazma","year":"1998","journal-title":"J Comput Biol"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1093\/bib\/5.3.217","article-title":"In silico representation and discovery of transcription factor binding sites","volume":"5","author":"Pavesi","year":"2004","journal-title":"Brief Bioinform"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/nrg1315","article-title":"Applied bioinformatics for the identification of regulatory elements","volume":"5","author":"Wasserman","year":"2004","journal-title":"Nat Rev Genet"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1101\/gr.4140006","article-title":"Locating mammalian transcription factor binding sites: a survey of computational and experimental techniques","volume":"16","author":"Elnitski","year":"2006","journal-title":"Genome Res"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1093\/nar\/13.9.3021","article-title":"Nomenclature for incompletely specified bases in nucleic acid sequences: recommendations 1984","volume":"13","year":"1985","journal-title":"Nucleic Acids Res"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/0076-6879(90)83015-2","article-title":"Consensus patterns in DNA","volume":"183","author":"Stormo","year":"1990","journal-title":"Methods Enzymol"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4878","DOI":"10.1093\/nar\/23.23.4878","article-title":"MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data","volume":"23","author":"Quandt","year":"1995","journal-title":"Nucleic Acids Res"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5393","DOI":"10.1093\/nar\/18.18.5393","article-title":"ARS binding factor 1 binds adjacent to RAP1 at the UASs of the yeast glycolytic genes PGK and PYK1","volume":"18","author":"Chambers","year":"1990","journal-title":"Nucleic Acids Res"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1093\/bioinformatics\/16.1.16","article-title":"DNA binding sites: representation and discovery","volume":"16","author":"Stormo","year":"2000","journal-title":"Bioinformatics"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3576","DOI":"10.1093\/nar\/gkg585","article-title":"MATCH: A tool for searching transcription factor binding sites in DNA sequences","volume":"31","author":"Kel","year":"2003","journal-title":"Nucleic Acids Res"},{"key":"ref_39","first-page":"365","article-title":"A method for identifying splice sites and translational start sites in eukaryotic mRNA","volume":"13","author":"Salzberg","year":"1997","journal-title":"Comput Appl Biosci"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1093\/nar\/30.5.1255","article-title":"Nucleotides of transcription factor binding sites exert interdependent effects on the binding affinities of transcription factors","volume":"30","author":"Bulyk","year":"2002","journal-title":"Nucleic Acids Res"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1093\/nar\/29.12.2471","article-title":"Non-independence of Mnt repressor-operator interaction determined by a new quantitative multiple fluorescence relative affinity (QuMFRA) assay","volume":"29","author":"Man","year":"2001","journal-title":"Nucleic Acids Res"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"S100","DOI":"10.1093\/bioinformatics\/18.suppl_2.S100","article-title":"Identifying transcription factor binding sites through Markov chain optimization","volume":"18","author":"Ellrott","year":"2002","journal-title":"Bioinformatics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1006\/jmbi.1997.0951","article-title":"Prediction of complete gene structures in human genomic DNA","volume":"268","author":"Burge","year":"1997","journal-title":"J Mol Biol"},{"key":"ref_44","unstructured":"Durbin, R., Eddy, S.R., Krogh, A., and Mitchison, G. (1998). Cambridge University Press."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1093\/bioinformatics\/17.12.1113","article-title":"A higher-order background model improves the detection of promoter regulatory elements by Gibbs sampling","volume":"17","author":"Thijs","year":"2001","journal-title":"Bioinformatics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2657","DOI":"10.1093\/bioinformatics\/bti410","article-title":"Identification of transcription factor binding sites with variable-order Bayesian networks","volume":"21","author":"Shani","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2933","DOI":"10.1093\/bioinformatics\/bti473","article-title":"MatInspector and beyond: promoter analysis based on transcription factor binding sites","volume":"21","author":"Cartharius","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"W432","DOI":"10.1093\/nar\/gki441","article-title":"P-Match: transcription factor binding site search by combining patterns and weight matrices","volume":"33","author":"Chekmenev","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2290","DOI":"10.1093\/nar\/gki519","article-title":"Computational technique for improvement of the position-weight matrices for the DNA\/protein binding sites","volume":"33","author":"Gershenzon","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.jmb.2004.02.048","article-title":"Constrained binding site diversity within families of transcription factors enhances pattern discovery bioinformatics","volume":"338","author":"Sandelin","year":"2004","journal-title":"J Mol Biol"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"i204","DOI":"10.1093\/bioinformatics\/bti1001","article-title":"Enhanced position weight matrices using mixture models","volume":"21","author":"Hannenhalli","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.cell.2007.12.014","article-title":"High-resolution mapping and characterization of open chromatin across the genome","volume":"132","author":"Boyle","year":"2008","journal-title":"Cell"},{"key":"ref_53","unstructured":"Genomatix. http:\/\/www.genomatix.de\/."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1006\/jmbi.2000.3589","article-title":"Highly specific localization of promoter regions in large genomic sequences by PromoterInspector: a novel context analysis approach","volume":"297","author":"Scherf","year":"2000","journal-title":"J Mol Biol"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1101\/gr.869803","article-title":"Dragon gene start finder: an advanced system for finding approximate locations of the start of gene transcriptional units","volume":"13","author":"Bajic","year":"2003","journal-title":"Genome Res"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.ygeno.2007.11.001","article-title":"EnsemPro: an ensemble approach to predicting transcription start sites in human genomic DNA sequences","volume":"91","author":"Won","year":"2008","journal-title":"Genomics"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/gb-2006-7-s1-s3","article-title":"Performance assessment of promoter predictions on ENCODE regions in the EGASP experiment","volume":"7","author":"Bajic","year":"2006","journal-title":"Genome Biol"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0097-8485(99)00015-7","article-title":"The biology of eukaryotic promoter prediction--a review","volume":"23","author":"Pedersen","year":"1999","journal-title":"Comput Chem"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.bbrc.2003.08.052","article-title":"Recent advances in computational promoter analysis in understanding the transcriptional regulatory network","volume":"309","author":"Qiu","year":"2003","journal-title":"Biochem Biophys Res Commun"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1093\/bib\/4.1.22","article-title":"The state of the art of mammalian promoter recognition","volume":"4","author":"Werner","year":"2003","journal-title":"Brief Bioinform"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.tig.2008.01.008","article-title":"The functional consequences of alternative promoter use in mammalian genomes","volume":"24","author":"Davuluri","year":"2008","journal-title":"Trends Genet"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/nrg2083","article-title":"Genome-wide transcription and the implications for genomic organization","volume":"8","author":"Kapranov","year":"2007","journal-title":"Nat Rev Genet"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/nrg2026","article-title":"Mammalian RNA polymerase II core promoters: insights from genome-wide studies","volume":"8","author":"Sandelin","year":"2007","journal-title":"Nat Rev Genet"},{"key":"ref_64","first-page":"81","article-title":"Identification of consensus patterns in unaligned DNA sequences known to be functionally related","volume":"6","author":"Hertz","year":"1990","journal-title":"Comput Appl Biosci"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1126\/science.8211139","article-title":"Detecting subtle sequence signals: a Gibbs sampling strategy for multiple alignment","volume":"262","author":"Lawrence","year":"1993","journal-title":"Science"},{"key":"ref_66","first-page":"28","article-title":"Fitting a mixture model by expectation maximization to discover motifs in biopolymers","volume":"2","author":"Bailey","year":"1994","journal-title":"Proc Int Conf Intell Syst Mol Biol"},{"key":"ref_67","unstructured":"Peters, H., and Vogel, Mia (2008). Machine Learning Research Progress, Nova Science Publishers, Inc."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1089\/106652700750050826","article-title":"Algorithms for extracting structured motifs using a suffix tree with an application to promoter and regulatory site consensus identification","volume":"7","author":"Marsan","year":"2000","journal-title":"J Comput Biol"},{"key":"ref_69","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":"ref_70","doi-asserted-by":"crossref","first-page":"D95","DOI":"10.1093\/nar\/gkj115","article-title":"A new generation of JASPAR, the open-access repository for transcription factor binding site profiles","volume":"34","author":"Vlieghe","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1093\/nar\/24.1.238","article-title":"TRANSFAC: a database on transcription factors and their DNA binding sites","volume":"24","author":"Wingender","year":"1996","journal-title":"Nucleic Acids Res"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1126\/science.1058040","article-title":"The sequence of the human genome","volume":"291","author":"Venter","year":"2001","journal-title":"Science"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/1471-2105-6-84","article-title":"Scoring functions for transcription factor binding site prediction","volume":"6","author":"Friberg","year":"2005","journal-title":"BMC Bioinformatics"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1748-7188-1-8","article-title":"Analysis of computational approaches for motif discovery","volume":"1","author":"Li","year":"2006","journal-title":"Algorithms Mol Biol"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1101\/gr.3578205","article-title":"Identification of functional transcription factor binding sites using closely related Saccharomyces species","volume":"15","author":"Doniger","year":"2005","journal-title":"Genome Res"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1126\/science.1084337","article-title":"Finding functional features in Saccharomyces genomes by phylogenetic footprinting","volume":"301","author":"Cliften","year":"2003","journal-title":"Science"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/nature02426","article-title":"Genome sequence of the Brown Norway rat yields insights into mammalian evolution","volume":"428","author":"Gibbs","year":"2004","journal-title":"Nature"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1101\/gr.926603","article-title":"LAGAN and Multi-LAGAN: efficient tools for large-scale multiple alignment of genomic DNA","volume":"13","author":"Brudno","year":"2003","journal-title":"Genome Res"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4673","DOI":"10.1093\/nar\/22.22.4673","article-title":"CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice","volume":"22","author":"Thompson","year":"1994","journal-title":"Nucleic Acids Res"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1093\/bioinformatics\/15.3.211","article-title":"DIALIGN 2: improvement of the segment-to-segment approach to multiple sequence alignment","volume":"15","author":"Morgenstern","year":"1999","journal-title":"Bioinformatics"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1006\/jmbi.2000.4042","article-title":"T-Coffee: A novel method for fast and accurate multiple sequence alignment","volume":"302","author":"Notredame","year":"2000","journal-title":"J Mol Biol"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/1471-2105-7-143","article-title":"Sigma: multiple alignment of weakly-conserved non-coding DNA sequence","volume":"7","author":"Siddharthan","year":"2006","journal-title":"BMC Bioinformatics"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1101\/gr.182901","article-title":"Surveying Saccharomyces genomes to identify functional elements by comparative DNA sequence analysis","volume":"11","author":"Cliften","year":"2001","journal-title":"Genome Res"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1101\/gr.197101","article-title":"Identifying functional elements by comparative DNA sequence analysis","volume":"11","author":"Tompa","year":"2001","journal-title":"Genome Res"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1101\/gr.6902","article-title":"Discovery of regulatory elements by a computational method for phylogenetic footprinting","volume":"12","author":"Blanchette","year":"2002","journal-title":"Genome Res"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1093\/nar\/29.3.774","article-title":"Phylogenetic footprinting of transcription factor binding sites in proteobacterial genomes","volume":"29","author":"McCue","year":"2001","journal-title":"Nucleic Acids Res"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1093\/bioinformatics\/btg329","article-title":"Combining phylogenetic data with co-regulated genes to identify regulatory motifs","volume":"19","author":"Wang","year":"2003","journal-title":"Bioinformatics"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1101\/gr.1642804","article-title":"CONREAL: conserved regulatory elements anchored alignment algorithm for identification of transcription factor binding sites by phylogenetic footprinting","volume":"14","author":"Berezikov","year":"2004","journal-title":"Genome Res"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3840","DOI":"10.1093\/nar\/gkg606","article-title":"FootPrinter: A program designed for phylogenetic footprinting","volume":"31","author":"Blanchette","year":"2003","journal-title":"Nucleic Acids Res"},{"key":"ref_90","unstructured":"Moses, A.M., Chiang, D.Y., and Eisen, M.B. (2004). Phylogenetic motif detection by expectation-maximization on evolutionary mixtures. Pac Symp Biocomput, 324\u2013335."},{"key":"ref_91","unstructured":"Munro, H.N. (1969). Mammalian protein metabolism, Academic Press."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/978-1-59745-514-5_19","article-title":"PhyME: a software tool for finding motifs in sets of orthologous sequences","volume":"395","author":"Sinha","year":"2007","journal-title":"Methods Mol Biol"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/1471-2105-5-170","article-title":"PhyME: a probabilistic algorithm for finding motifs in sets of orthologous sequences","volume":"5","author":"Sinha","year":"2004","journal-title":"BMC Bioinformatics"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e1000156","DOI":"10.1371\/journal.pcbi.1000156","article-title":"PhyloGibbs-MP: module prediction and discriminative motif-finding by Gibbs sampling","volume":"4","author":"Siddharthan","year":"2008","journal-title":"PLoS Comput Biol"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1371\/journal.pcbi.0010067","article-title":"PhyloGibbs: a Gibbs sampling motif finder that incorporates phylogeny","volume":"1","author":"Siddharthan","year":"2005","journal-title":"PLoS Comput Biol"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"i292","DOI":"10.1093\/bioinformatics\/btg1040","article-title":"A probabilistic method to detect regulatory modules","volume":"19","author":"Sinha","year":"2003","journal-title":"Bioinformatics"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1007\/BF01734359","article-title":"Evolutionary trees from DNA sequences: a maximum likelihood approach","volume":"17","author":"Felsenstein","year":"1981","journal-title":"J Mol Evol"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"R98","DOI":"10.1186\/gb-2004-5-12-r98","article-title":"MONKEY: identifying conserved transcription-factor binding sites in multiple alignments using a binding site-specific evolutionary model","volume":"5","author":"Moses","year":"2004","journal-title":"Genome Biol"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1007\/BF02101694","article-title":"Dating of the human-ape splitting by a molecular clock of mitochondrial DNA","volume":"22","author":"Hasegawa","year":"1985","journal-title":"J Mol Evol"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1186\/1471-2105-7-266","article-title":"Phylogeny based discovery of regulatory elements","volume":"7","author":"Gertz","year":"2006","journal-title":"BMC Bioinformatics"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1748-7188-2-1","article-title":"PhyloScan: identification of transcription factor binding sites using cross-species evidence","volume":"2","author":"Carmack","year":"2007","journal-title":"Algorithms Mol Biol"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nature02800","article-title":"Transcriptional regulatory code of a eukaryotic genome","volume":"431","author":"Harbison","year":"2004","journal-title":"Nature"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"R2","DOI":"10.1186\/gb-2008-9-1-r2","article-title":"High-resolution analysis of condition-specific regulatory modules in Saccharomyces cerevisiae","volume":"9","author":"Lee","year":"2008","journal-title":"Genome Biol"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/msb4100140","article-title":"Inferring condition-specific transcription factor function from DNA binding and gene expression data","volume":"3","author":"McCord","year":"2007","journal-title":"Mol Syst Biol"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/msb4100114","article-title":"Tissue-specific regulatory elements in mammalian promoters","volume":"3","author":"Smith","year":"2007","journal-title":"Mol Syst Biol"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1186\/1471-2105-8-437","article-title":"Identification of tissue-specific cis-regulatory modules based on interactions between transcription factors","volume":"8","author":"Yu","year":"2007","journal-title":"BMC Bioinformatics"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/S0168-9525(02)02591-X","article-title":"Regulatory context is a crucial part of gene function","volume":"18","author":"Fessele","year":"2002","journal-title":"Trends Genet"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/1471-2105-5-18","article-title":"Quantifying the relationship between co-expression, co-regulation and gene function","volume":"5","author":"Allocco","year":"2004","journal-title":"BMC Bioinformatics"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"395","DOI":"10.3233\/ISB-00143","article-title":"Genome-wide prediction and analysis of function-specific transcription factor binding sites","volume":"4","author":"Long","year":"2004","journal-title":"In Silico Biol"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1006\/jmbi.1997.1140","article-title":"A novel method to develop highly specific models for regulatory units detects a new LTR in GenBank which contains a functional promoter","volume":"270","author":"Frech","year":"1997","journal-title":"J Mol Biol"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"3666","DOI":"10.1093\/nar\/gkg540","article-title":"Cluster-Buster: Finding dense clusters of motifs in DNA sequences","volume":"31","author":"Frith","year":"2003","journal-title":"Nucleic Acids Res"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"12114","DOI":"10.1073\/pnas.0402858101","article-title":"CisModule: de novo discovery of cis-regulatory modules by hierarchical mixture modeling","volume":"101","author":"Zhou","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"W195","DOI":"10.1093\/nar\/gkh387","article-title":"MSCAN: identification of functional clusters of transcription factor binding sites","volume":"32","author":"Alkema","year":"2004","journal-title":"Nucleic Acids Res"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2858","DOI":"10.1093\/bioinformatics\/btl499","article-title":"Identifying cis-regulatory modules by combining comparative and compositional analysis of DNA","volume":"22","author":"Pierstorff","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"R66","DOI":"10.1186\/gb-2008-9-4-r66","article-title":"ModuleMiner - improved computational detection of cis-regulatory modules: are there different modes of gene regulation in embryonic development and adult tissues?","volume":"9","author":"Aerts","year":"2008","journal-title":"Genome Biol"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"W133","DOI":"10.1093\/nar\/gkn300","article-title":"DiRE: identifying distant regulatory elements of co-expressed genes","volume":"36","author":"Gotea","year":"2008","journal-title":"Nucleic Acids Res"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"W541","DOI":"10.1093\/nar\/gkl342","article-title":"Composite Module Analyst: identification of transcription factor binding site combinations using genetic algorithm","volume":"34","author":"Waleev","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/nbt1098-939","article-title":"Finding DNA regulatory motifs within unaligned noncoding sequences clustered by whole-genome mRNA quantitation","volume":"16","author":"Roth","year":"1998","journal-title":"Nat Biotechnol"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/10343","article-title":"Systematic determination of genetic network architecture","volume":"22","author":"Tavazoie","year":"1999","journal-title":"Nat Genet"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/35015701","article-title":"Genomics, gene expression and DNA arrays","volume":"405","author":"Lockhart","year":"2000","journal-title":"Nature"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/nrg2228","article-title":"Gene regulation: The many paths to coexpression","volume":"8","author":"Flintoft","year":"2007","journal-title":"Nature Reviews Genetics"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.ygeno.2005.11.015","article-title":"Condition-specific coregulation with cis-regulatory motifs and modules in the mouse genome","volume":"87","author":"Choi","year":"2006","journal-title":"Genomics"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.ygeno.2005.11.011","article-title":"Comprehensive analysis of pathway or functionally related gene expression in the National Cancer Institute's anticancer screen","volume":"87","author":"Huang","year":"2006","journal-title":"Genomics"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/ng1165","article-title":"Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data","volume":"34","author":"Segal","year":"2003","journal-title":"Nat Genet"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1101\/gr.947203","article-title":"Genome-wide in silico identification of transcriptional regulators controlling the cell cycle in human cells","volume":"13","author":"Elkon","year":"2003","journal-title":"Genome Res"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/1471-2105-6-110","article-title":"Ab initio identification of putative human transcription factor binding sites by comparative genomics","volume":"6","author":"Cora","year":"2005","journal-title":"BMC Bioinformatics"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1186\/1471-2105-7-396","article-title":"Predicting transcription factor binding sites using local over-representation and comparative genomics","volume":"7","author":"Defrance","year":"2006","journal-title":"BMC Bioinformatics"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/1471-2105-7-160","article-title":"More robust detection of motifs in coexpressed genes by using phylogenetic information","volume":"7","author":"Monsieurs","year":"2006","journal-title":"BMC Bioinformatics"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"R103","DOI":"10.1186\/gb-2006-7-11-r103","article-title":"Identification of novel regulatory modules in dicotyledonous plants using expression data and comparative genomics","volume":"7","author":"Vandepoele","year":"2006","journal-title":"Genome Biol"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1101\/gr.3642605","article-title":"Evaluation of regulatory potential and conservation scores for detecting cis-regulatory modules in aligned mammalian genome sequences","volume":"15","author":"King","year":"2005","journal-title":"Genome Res"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1101\/gr.1976004","article-title":"Regulatory potential scores from genome-wide three-way alignments of human, mouse, and rat","volume":"14","author":"Kolbe","year":"2004","journal-title":"Genome Res"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1101\/gr.4537706","article-title":"ESPERR: learning strong and weak signals in genomic sequence alignments to identify functional elements","volume":"16","author":"Taylor","year":"2006","journal-title":"Genome Res"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1101\/gr.5353806","article-title":"Experimental validation of predicted mammalian erythroid cis-regulatory modules","volume":"16","author":"Wang","year":"2006","journal-title":"Genome Res"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.tig.2005.07.011","article-title":"Multievidence microarray mining","volume":"21","author":"Seifert","year":"2005","journal-title":"Trends Genet"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/978-1-59745-547-3_4","article-title":"From promoter analysis to transcriptional regulatory network prediction using PAINT","volume":"408","author":"Gonye","year":"2007","journal-title":"Methods Mol Biol"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1089\/153623103322452378","article-title":"PAINT: a promoter analysis and interaction network generation tool for gene regulatory network identification","volume":"7","author":"Vadigepalli","year":"2003","journal-title":"Omics"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"W213","DOI":"10.1093\/nar\/gkh402","article-title":"CARRIE web service: automated transcriptional regulatory network inference and interactive analysis","volume":"32","author":"Haverty","year":"2004","journal-title":"Nucleic Acids Res"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1093\/nar\/gkh183","article-title":"Computational inference of transcriptional regulatory networks from expression profiling and transcription factor binding site identification","volume":"32","author":"Haverty","year":"2004","journal-title":"Nucleic Acids Res"}],"container-title":["Algorithms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4893\/2\/1\/582\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T22:10:06Z","timestamp":1760220606000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4893\/2\/1\/582"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,3,24]]},"references-count":138,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2009,3]]}},"alternative-id":["a2010582"],"URL":"https:\/\/doi.org\/10.3390\/a2010582","relation":{},"ISSN":["1999-4893"],"issn-type":[{"type":"electronic","value":"1999-4893"}],"subject":[],"published":{"date-parts":[[2009,3,24]]}}}