{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T14:05:16Z","timestamp":1761919516375},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"23","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: ChIP-seq and ChIP-chip experiments have been widely used to identify transcription factor (TF) binding sites and target genes. Conventionally, a fairly \u2018simple\u2019 approach is employed for target gene identification e.g. finding genes with binding sites within 2 kb of a transcription start site (TSS). However, this does not take into account the number of sites upstream of the TSS, their exact positioning or the fact that different TFs appear to act at different characteristic distances from the TSS.<\/jats:p>\n               <jats:p>Results: Here we propose a probabilistic model called target identification from profiles (TIP) that quantitatively measures the regulatory relationships between TFs and target genes. For each TF, our model builds a characteristic, averaged profile of binding around the TSS and then uses this to weight the sites associated with a given gene, providing a continuous-valued \u2018regulatory\u2019 score relating each TF and potential target. Moreover, the score can readily be turned into a ranked list of target genes and an estimate of significance, which is useful for case-dependent downstream analysis.<\/jats:p>\n               <jats:p>Conclusion: We show the advantages of TIP by comparing it to the \u2018simple\u2019 approach on several representative datasets, using motif occurrence and relationship to knock-out experiments as metrics of validation. Moreover, we show that the probabilistic model is not as sensitive to various experimental parameters (including sequencing depth and peak-calling method) as the simple approach; in fact, the lesser dependence on sequencing depth potentially utilizes the result of a ChIP-seq experiment in a more \u2018cost-effective\u2019 manner.<\/jats:p>\n               <jats:p>Contact: \u00a0mark.gerstein@yale.edu<\/jats:p>\n               <jats:p>Supplementary Information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btr552","type":"journal-article","created":{"date-parts":[[2011,10,30]],"date-time":"2011-10-30T01:06:33Z","timestamp":1319936793000},"page":"3221-3227","source":"Crossref","is-referenced-by-count":51,"title":["TIP: A probabilistic method for identifying transcription factor target genes from ChIP-seq binding profiles"],"prefix":"10.1093","volume":"27","author":[{"given":"Chao","family":"Cheng","sequence":"first","affiliation":[{"name":"1 Program of Computational Biology and Bioinformatics, 2Department of Molecular Biophysics and Biochemistry and 3Department of Computer Science, Yale University, New Haven, CT 06511, USA"},{"name":"1 Program of Computational Biology and Bioinformatics, 2Department of Molecular Biophysics and Biochemistry and 3Department of Computer Science, Yale University, New Haven, CT 06511, USA"}]},{"given":"Renqiang","family":"Min","sequence":"additional","affiliation":[{"name":"1 Program of Computational Biology and Bioinformatics, 2Department of Molecular Biophysics and Biochemistry and 3Department of Computer Science, Yale University, New Haven, CT 06511, USA"},{"name":"1 Program of Computational Biology and Bioinformatics, 2Department of Molecular Biophysics and Biochemistry and 3Department of Computer Science, Yale University, New Haven, CT 06511, USA"}]},{"given":"Mark","family":"Gerstein","sequence":"additional","affiliation":[{"name":"1 Program of Computational Biology and Bioinformatics, 2Department of Molecular Biophysics and Biochemistry and 3Department of Computer Science, Yale University, New Haven, CT 06511, USA"},{"name":"1 Program of Computational Biology and Bioinformatics, 2Department of Molecular Biophysics and Biochemistry and 3Department of Computer Science, Yale University, New Haven, CT 06511, USA"},{"name":"1 Program of Computational Biology and Bioinformatics, 2Department of Molecular Biophysics and Biochemistry and 3Department of Computer Science, Yale University, New Haven, CT 06511, USA"}]}],"member":"286","published-online":{"date-parts":[[2011,10,29]]},"reference":[{"key":"2023012511050475100_B1","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":"2023012511050475100_B2","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/nature05874","article-title":"Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project","volume":"447","author":"Birney","year":"2007","journal-title":"Nature"},{"key":"2023012511050475100_B3","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.cell.2005.08.020","article-title":"Core transcriptional regulatory circuitry in human embryonic stem cells","volume":"122","author":"Boyer","year":"2005","journal-title":"Cell"},{"key":"2023012511050475100_B4","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.cell.2008.04.043","article-title":"Integration of external signaling pathways with the core transcriptional network in embryonic stem cells","volume":"133","author":"Chen","year":"2008","journal-title":"Cell"},{"key":"2023012511050475100_B5","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1101\/gr.096305.109","article-title":"Integrating multiple evidence sources to predict transcription factor binding in the human genome","volume":"20","author":"Ernst","year":"2010","journal-title":"Genome Res."},{"key":"2023012511050475100_B6","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1126\/science.1196914","article-title":"Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project","volume":"330","author":"Gerstein","year":"2010","journal-title":"Science"},{"key":"2023012511050475100_B7","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":"2023012511050475100_B8","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1038\/nbt.1505","article-title":"An integrated software system for analyzing ChIP-chip and ChIP-seq data","volume":"26","author":"Ji","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"2023012511050475100_B9","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1126\/science.1141319","article-title":"Genome-wide mapping of in vivo protein-DNA interactions","volume":"316","author":"Johnson","year":"2007","journal-title":"Science"},{"key":"2023012511050475100_B10","doi-asserted-by":"crossref","first-page":"e1001290","DOI":"10.1371\/journal.pgen.1001290","article-title":"Quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development","volume":"7","author":"Kaplan","year":"2011","journal-title":"PLoS Genet."},{"key":"2023012511050475100_B11","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1101\/gr.229102","article-title":"The human genome browser at UCSC","volume":"12","author":"Kent","year":"2002","journal-title":"Genome Res."},{"key":"2023012511050475100_B12","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1038\/nbt.1508","article-title":"Design and analysis of ChIP-seq experiments for DNA-binding proteins","volume":"26","author":"Kharchenko","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"2023012511050475100_B13","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.cell.2008.02.039","article-title":"An extended transcriptional network for pluripotency of embryonic stem cells","volume":"132","author":"Kim","year":"2008","journal-title":"Cell"},{"key":"2023012511050475100_B14","doi-asserted-by":"crossref","first-page":"e27","DOI":"10.1371\/journal.pbio.0060027","article-title":"Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm","volume":"6","author":"Li","year":"2008","journal-title":"PLoS Biol."},{"key":"2023012511050475100_B15","doi-asserted-by":"crossref","first-page":"R80","DOI":"10.1186\/gb-2009-10-7-r80","article-title":"Developmental roles of 21 Drosophila transcription factors are determined by quantitative differences in binding to an overlapping set of thousands of genomic regions","volume":"10","author":"MacArthur","year":"2009","journal-title":"Genome Biol."},{"key":"2023012511050475100_B16","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.cell.2008.07.020","article-title":"Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells","volume":"134","author":"Marson","year":"2008","journal-title":"Cell"},{"key":"2023012511050475100_B17","doi-asserted-by":"crossref","first-page":"D204","DOI":"10.1093\/nar\/gkp1019","article-title":"PANTHER version 7: improved phylogenetic trees, orthologs and collaboration with the Gene Ontology Consortium","volume":"38","author":"Mi","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2023012511050475100_B18","doi-asserted-by":"crossref","first-page":"e15092","DOI":"10.1371\/journal.pone.0015092","article-title":"Efficient double fragmentation ChIP-seq provides nucleotide resolution protein-DNA binding profiles","volume":"5","author":"Mokry","year":"2010","journal-title":"PLoS One"},{"key":"2023012511050475100_B19","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1186\/1471-2105-9-523","article-title":"Empirical methods for controlling false positives and estimating confidence in ChIP-Seq peaks","volume":"9","author":"Nix","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"2023012511050475100_B20","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nrg2641","article-title":"ChIP-seq: advantages and challenges of a maturing technology","volume":"10","author":"Park","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"2023012511050475100_B21","doi-asserted-by":"crossref","first-page":"S22","DOI":"10.1038\/nmeth.1371","article-title":"Computation for ChIP-seq and RNA-seq studies","volume":"6","author":"Pepke","year":"2009","journal-title":"Nat. Methods"},{"key":"2023012511050475100_B22","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1093\/bioinformatics\/btq405","article-title":"Genome-wide histone acetylation data improve prediction of mammalian transcription factor binding sites","volume":"26","author":"Ramsey","year":"2010","journal-title":"Bioinformatics"},{"key":"2023012511050475100_B23","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1126\/science.1198374","article-title":"Identification of functional elements and regulatory circuits by Drosophila modENCODE","volume":"330","author":"Roy","year":"2010","journal-title":"Science"},{"key":"2023012511050475100_B24","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/nbt.1518","article-title":"PeakSeq enables systematic scoring of ChIP-seq experiments relative to controls","volume":"27","author":"Rozowsky","year":"2009","journal-title":"Nat. Biotechnol."},{"key":"2023012511050475100_B25","doi-asserted-by":"crossref","first-page":"3943","DOI":"10.1128\/MCB.00118-10","article-title":"Genome-wide analysis of estrogen receptor alpha DNA binding and tethering mechanisms identifies Runx1 as a novel tethering factor in receptor-mediated transcriptional activation","volume":"30","author":"Stender","year":"2010","journal-title":"Mol. Cell Biol."},{"key":"2023012511050475100_B26","doi-asserted-by":"crossref","first-page":"9440","DOI":"10.1073\/pnas.1530509100","article-title":"Statistical significance for genomewide studies","volume":"100","author":"Storey","year":"2003","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012511050475100_B27","doi-asserted-by":"crossref","first-page":"e113","DOI":"10.1093\/nar\/gkp536","article-title":"Extracting transcription factor targets from ChIP-Seq data","volume":"37","author":"Tuteja","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2023012511050475100_B28","doi-asserted-by":"crossref","first-page":"i165","DOI":"10.1093\/bioinformatics\/btn154","article-title":"Predicting functional transcription factor binding through alignment-free and affinity-based analysis of orthologous promoter sequences","volume":"24","author":"Ward","year":"2008","journal-title":"Bioinformatics"},{"key":"2023012511050475100_B29","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.immuni.2010.06.003","article-title":"Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation","volume":"32","author":"Wei","year":"2010","journal-title":"Immunity"},{"key":"2023012511050475100_B30","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1093\/nar\/gkn866","article-title":"High-throughput chromatin information enables accurate tissue-specific prediction of transcription factor binding sites","volume":"37","author":"Whitington","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2023012511050475100_B31","doi-asserted-by":"crossref","first-page":"e11471","DOI":"10.1371\/journal.pone.0011471","article-title":"Evaluation of algorithm performance in ChIP-seq peak detection","volume":"5","author":"Wilbanks","year":"2010","journal-title":"PLoS One"},{"key":"2023012511050475100_B32","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":"2023012511050475100_B33","doi-asserted-by":"crossref","first-page":"R7","DOI":"10.1186\/gb-2010-11-1-r7","article-title":"Genome-wide prediction of transcription factor binding sites using an integrated model","volume":"11","author":"Won","year":"2010","journal-title":"Genome Biol."},{"key":"2023012511050475100_B34","doi-asserted-by":"crossref","first-page":"R137","DOI":"10.1186\/gb-2008-9-9-r137","article-title":"Model-based analysis of ChIP-Seq (MACS)","volume":"9","author":"Zhang","year":"2008","journal-title":"Genome Biol."},{"key":"2023012511050475100_B35","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1101\/gr.5573107","article-title":"Statistical analysis of the genomic distribution and correlation of regulatory elements in the ENCODE regions","volume":"17","author":"Zhang","year":"2007","journal-title":"Genome Res."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/27\/23\/3221\/48861925\/bioinformatics_27_23_3221.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/27\/23\/3221\/48861925\/bioinformatics_27_23_3221.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T11:10:03Z","timestamp":1674645003000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/27\/23\/3221\/234205"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,10,29]]},"references-count":35,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2011,12,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btr552","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2011,12,1]]},"published":{"date-parts":[[2011,10,29]]}}}