{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T22:13:42Z","timestamp":1778710422449,"version":"3.51.4"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Motivation: Sequence-specific transcription factors (TFs) regulate the expression of their target genes through interactions with specific DNA-binding sites in the genome. Data on TF-DNA binding specificities are essential for understanding how regulatory specificity is achieved.<\/jats:p><jats:p>Results: Numerous studies have used universal protein-binding microarray (PBM) technology to determine the in vitro binding specificities of hundreds of TFs for all possible 8 bp sequences (8mers). We have developed a Bayesian analysis of variance (ANOVA) model that decomposes these 8mer data into background noise, TF familywise effects and effects due to the particular TF. Adjusting for background noise improves PBM data quality and concordance with in vivo TF binding data. Moreover, our model provides simultaneous identification of TF subclasses and their shared sequence preferences, and also of 8mers bound preferentially by individual members of TF subclasses. Such results may aid in deciphering cis-regulatory codes and determinants of protein\u2013DNA binding specificity.<\/jats:p><jats:p>Availability and implementation: Source code, compiled code and R and Python scripts are available from http:\/\/thebrain.bwh.harvard.edu\/hierarchicalANOVA.<\/jats:p><jats:p>Contact: \u00a0bojiang83@gmail.com or mlbulyk@receptor.med.harvard.edu<\/jats:p><jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btt152","type":"journal-article","created":{"date-parts":[[2013,4,5]],"date-time":"2013-04-05T03:00:54Z","timestamp":1365130854000},"page":"1390-1398","source":"Crossref","is-referenced-by-count":16,"title":["Bayesian hierarchical model of protein-binding microarray<i>k<\/i>-mer data reduces noise and identifies transcription factor subclasses and preferred<i>k<\/i>-mers"],"prefix":"10.1093","volume":"29","author":[{"given":"Bo","family":"Jiang","sequence":"first","affiliation":[{"name":"1 Department of Statistics, Harvard University, Cambridge, MA 02138, USA, 2Division of Genetics, Department of Medicine, 3Department of Pathology, Brigham and Women\u2019s Hospital and Harvard Medical School and 4Harvard-MIT Division of Health Sciences and Technology (HST), Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun S.","family":"Liu","sequence":"additional","affiliation":[{"name":"1 Department of Statistics, Harvard University, Cambridge, MA 02138, USA, 2Division of Genetics, Department of Medicine, 3Department of Pathology, Brigham and Women\u2019s Hospital and Harvard Medical School and 4Harvard-MIT Division of Health Sciences and Technology (HST), Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martha L.","family":"Bulyk","sequence":"additional","affiliation":[{"name":"1 Department of Statistics, Harvard University, Cambridge, MA 02138, USA, 2Division of Genetics, Department of Medicine, 3Department of Pathology, Brigham and Women\u2019s Hospital and Harvard Medical School and 4Harvard-MIT Division of Health Sciences and Technology (HST), Harvard Medical School, Boston, MA 02115, USA"},{"name":"1 Department of Statistics, Harvard University, Cambridge, MA 02138, USA, 2Division of Genetics, Department of Medicine, 3Department of Pathology, Brigham and Women\u2019s Hospital and Harvard Medical School and 4Harvard-MIT Division of Health Sciences and Technology (HST), Harvard Medical School, Boston, MA 02115, USA"},{"name":"1 Department of Statistics, Harvard University, Cambridge, MA 02138, USA, 2Division of Genetics, Department of Medicine, 3Department of Pathology, Brigham and Women\u2019s Hospital and Harvard Medical School and 4Harvard-MIT Division of Health Sciences and Technology (HST), Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,4,4]]},"reference":[{"key":"2023062610160127600_btt152-B46","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1002\/jcb.20352","article-title":"Transcriptional enhancers: Intelligent enhanceosomes or flexible billboards?","volume":"94","author":"Arnosti","year":"2005","journal-title":"J. Cell. Biochem."},{"key":"2023062610160127600_btt152-B1","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.molcel.2008.11.020","article-title":"A library of yeast transcription factor motifs reveals a widespread function for Rsc3 in targeting nucleosome exclusion at promoters","volume":"32","author":"Badis","year":"2008","journal-title":"Mol. Cell"},{"key":"2023062610160127600_btt152-B2","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1126\/science.1162327","article-title":"Diversity and complexity in DNA recognition by transcription factors","volume":"324","author":"Badis","year":"2009","journal-title":"Science"},{"key":"2023062610160127600_btt152-B3","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0092-8674(04)00304-6","article-title":"Predicting gene expression from sequence","volume":"117","author":"Beer","year":"2004","journal-title":"Cell"},{"key":"2023062610160127600_btt152-B4","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Series B Stat. Methodol."},{"key":"2023062610160127600_btt152-B5","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1002\/bies.10073","article-title":"Is there a code for protein-DNA recognition? Probab(ilistical)ly \u2026","volume":"24","author":"Benos","year":"2002","journal-title":"Bioessays"},{"key":"2023062610160127600_btt152-B6","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":"2023062610160127600_btt152-B7","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1038\/nbt1246","article-title":"Compact, universal DNA microarrays to comprehensively determine transcription-factor binding site specificities","volume":"24","author":"Berger","year":"2006","journal-title":"Nat. Biotechnol."},{"key":"2023062610160127600_btt152-B8","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1016\/j.cell.2008.05.024","article-title":"Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences","volume":"133","author":"Berger","year":"2008","journal-title":"Cell"},{"key":"2023062610160127600_btt152-B9","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1214\/ss\/1032280304","article-title":"Bioequivalence trials, intersection-union tests and equivalence confidence sets","volume":"11","author":"Berger","year":"1996","journal-title":"Stat. Sci."},{"key":"2023062610160127600_btt152-B10","doi-asserted-by":"crossref","first-page":"7158","DOI":"10.1073\/pnas.111163698","article-title":"Exploring the DNA-binding specificities of zinc fingers with DNA microarrays","volume":"98","author":"Bulyk","year":"2001","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023062610160127600_btt152-B11","first-page":"65","article-title":"Gene regulatory networks","volume-title":"Handbook of Systems Biology: Concepts and Insights","author":"Bulyk","year":"2012"},{"key":"2023062610160127600_btt152-B12","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1242\/dev.077362","article-title":"Molecular mechanism underlying the regulatory specificity of a Drosophila homeodomain protein that specifies myoblast identity","volume":"139","author":"Busser","year":"2012","journal-title":"Development"},{"key":"2023062610160127600_btt152-B13","doi-asserted-by":"crossref","first-page":"e1001165","DOI":"10.1371\/journal.ppat.1001165","article-title":"Identification and genome-wide prediction of DNA binding specificities for the ApiAP2 family of regulators from the malaria parasite","volume":"6","author":"Campbell","year":"2010","journal-title":"PLoS Pathog."},{"key":"2023062610160127600_btt152-B14","first-page":"93","article-title":"Biclustering of expression data","volume":"8","author":"Cheng","year":"2000","journal-title":"Proc. Int. Conf. Intell. Syst. Mol. Biol."},{"key":"2023062610160127600_btt152-B15","doi-asserted-by":"crossref","first-page":"4553","DOI":"10.1093\/nar\/gkr070","article-title":"Using a structural and logics systems approach to infer bHLH-DNA binding specificity determinants","volume":"39","author":"De Masi","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"2023062610160127600_btt152-B16","doi-asserted-by":"crossref","first-page":"14863","DOI":"10.1073\/pnas.95.25.14863","article-title":"Cluster analysis and display of genome-wide expression patterns","volume":"95","author":"Eisen","year":"1998","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023062610160127600_btt152-B17","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/msb.2009.97","article-title":"Deciphering a transcriptional regulatory code: modeling short-range repression in the Drosophila embryo","volume":"6","author":"Fakhouri","year":"2010","journal-title":"Mol. Syst. Biol."},{"key":"2023062610160127600_btt152-B18","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":"2023062610160127600_btt152-B19","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1109\/TPAMI.1984.4767596","article-title":"Stochastic relaxation, Gibbs distributions, and the Bayesian restoration of images","volume":"6","author":"Geman","year":"1984","journal-title":"IEEE Trans. Pattern Anal. Mach. Intell."},{"key":"2023062610160127600_btt152-B20","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1101\/gr.094144.109","article-title":"Distinguishing direct versus indirect transcription factor-DNA interactions","volume":"19","author":"Gord\u00e2n","year":"2009","journal-title":"Genome Res."},{"key":"2023062610160127600_btt152-B21","doi-asserted-by":"crossref","first-page":"R125","DOI":"10.1186\/gb-2011-12-12-r125","article-title":"Curated collection of yeast transcription factor DNA binding specificity data reveals novel structural and gene regulatory insights","volume":"12","author":"Gord\u00e2n","year":"2011","journal-title":"Genome Biol."},{"key":"2023062610160127600_btt152-B22","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.cell.2009.04.058","article-title":"A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors","volume":"138","author":"Grove","year":"2009","journal-title":"Cell"},{"key":"2023062610160127600_btt152-B23","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1093\/bioinformatics\/bts438","article-title":"iBBiG: iterative binary bi-clustering of gene sets","volume":"28","author":"Gusenleitner","year":"2012","journal-title":"Bioinformatics"},{"key":"2023062610160127600_btt152-B24","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":"2023062610160127600_btt152-B25","doi-asserted-by":"crossref","first-page":"e1000778","DOI":"10.1371\/journal.pgen.1000778","article-title":"DNA specificity determinants associate with distinct transcription factor functions","volume":"5","author":"Hollenhorst","year":"2009","journal-title":"PLoS Genet."},{"key":"2023062610160127600_btt152-B26","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1093\/biostatistics\/kxj037","article-title":"Adjusting batch effects in microarray expression data using empirical Bayes methods","volume":"8","author":"Johnson","year":"2007","journal-title":"Biostatistics"},{"key":"2023062610160127600_btt152-B27","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":"2023062610160127600_btt152-B28","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1371\/journal.pgen.0030161","article-title":"Capturing heterogeneity in gene expression studies by surrogate variable analysis","volume":"3","author":"Leek","year":"2007","journal-title":"PLoS Genet."},{"key":"2023062610160127600_btt152-B29","doi-asserted-by":"crossref","first-page":"18718","DOI":"10.1073\/pnas.0808709105","article-title":"A general framework for multiple testing dependence","volume":"105","author":"Leek","year":"2008","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023062610160127600_btt152-B30","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/nrg2825","article-title":"Tackling the widespread and critical impact of batch effects in high-throughput data","volume":"11","author":"Leek","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"2023062610160127600_btt152-B31","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1093\/bioinformatics\/bts034","article-title":"The sva package for removing batch effects and other unwanted variation in high-throughput experiments","volume":"28","author":"Leek","year":"2012","journal-title":"Bioinformatics"},{"key":"2023062610160127600_btt152-B32","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1080\/01621459.1994.10476829","article-title":"The collapsed Gibbs sampler in Bayesian computations with applications to a gene regulation problem","volume":"89","author":"Liu","year":"1994","journal-title":"J. Am. Stat. Assoc."},{"key":"2023062610160127600_btt152-B33","volume-title":"Monte Carlo Strategies in Scientific Computing","author":"Liu","year":"2008"},{"key":"2023062610160127600_btt152-B34","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2000-1-1-reviews001","article-title":"An overview of the structures of protein-DNA complexes","volume":"1","author":"Luscombe","year":"2000","journal-title":"Genome Biol."},{"key":"2023062610160127600_btt152-B35","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":"2023062610160127600_btt152-B36","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1063\/1.1699114","article-title":"Equations of state calculations by fast computing machines","volume":"21","author":"Metropolis","year":"1953","journal-title":"J. Chem. Phys."},{"key":"2023062610160127600_btt152-B37","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1016\/j.cell.2008.05.023","article-title":"Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites","volume":"133","author":"Noyes","year":"2008","journal-title":"Cell"},{"key":"2023062610160127600_btt152-B38","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1089\/cmb.2007.0114","article-title":"Design of compact, universal DNA microarrays for protein binding microarray experiments","volume":"15","author":"Philippakis","year":"2008","journal-title":"J. Comput. Biol."},{"key":"2023062610160127600_btt152-B39","doi-asserted-by":"crossref","first-page":"D124","DOI":"10.1093\/nar\/gkq992","article-title":"UniPROBE, update 2011: expanded content and search tools in the online database of protein-binding microarray data on protein-DNA interactions","volume":"39","author":"Robasky","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"2023062610160127600_btt152-B40","doi-asserted-by":"crossref","first-page":"6097","DOI":"10.1093\/nar\/18.20.6097","article-title":"Sequence logos: a new way to display consensus sequences","volume":"18","author":"Schneider","year":"1990","journal-title":"Nucleic Acids Res."},{"key":"2023062610160127600_btt152-B41","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S1097-2765(03)00500-8","article-title":"Immunity regulatory DNAs share common organizational features in Drosophila","volume":"13","author":"Senger","year":"2004","journal-title":"Mol. Cell"},{"key":"2023062610160127600_btt152-B42","doi-asserted-by":"crossref","first-page":"12357","DOI":"10.1073\/pnas.91.26.12357","article-title":"DNA recognition code of transcription factors in the helix-turn-helix, probe helix, hormone receptor, and zinc finger families","volume":"91","author":"Suzuki","year":"1994","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023062610160127600_btt152-B43","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/nmeth.1188","article-title":"Systematic identification of mammalian regulatory motifs\u2019 target genes and their functions","volume":"5","author":"Warner","year":"2008","journal-title":"Nat. Methods"},{"key":"2023062610160127600_btt152-B44","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1038\/emboj.2010.106","article-title":"Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo","volume":"29","author":"Wei","year":"2010","journal-title":"EMBO J."},{"key":"2023062610160127600_btt152-B45","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1101\/gr.090233.108","article-title":"High-resolution DNA-binding specificity analysis of yeast transcription factors","volume":"19","author":"Zhu","year":"2009","journal-title":"Genome Res."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/29\/11\/1390\/50701273\/bioinformatics_29_11_1390.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/29\/11\/1390\/50701273\/bioinformatics_29_11_1390.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T10:35:13Z","timestamp":1715164513000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/29\/11\/1390\/220130"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,4,4]]},"references-count":46,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2013,6,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btt152","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2013,6,1]]},"published":{"date-parts":[[2013,4,4]]}}}