{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T06:26:47Z","timestamp":1772519207552,"version":"3.50.1"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2018,8,28]],"date-time":"2018-08-28T00:00:00Z","timestamp":1535414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"National Science Foundation ABI Innovation","award":["DBI1564466"],"award-info":[{"award-number":["DBI1564466"]}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM059055"],"award-info":[{"award-number":["GM059055"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Penn State Huck Graduate Research Innovation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>Regulatory proteins associate with the genome either by directly binding cognate DNA motifs or via protein\u2013protein interactions with other regulators. Each recruitment mechanism may be associated with distinct motifs and may also result in distinct characteristic patterns in high-resolution protein\u2013DNA binding assays. For example, the ChIP-exo protocol precisely characterizes protein\u2013DNA crosslinking patterns by combining chromatin immunoprecipitation (ChIP) with 5\u2032 \u2192 3\u2032 exonuclease digestion. Since different regulatory complexes will result in different protein\u2013DNA crosslinking signatures, analysis of ChIP-exo tag enrichment patterns should enable detection of multiple protein\u2013DNA binding modes for a given regulatory protein. However, current ChIP-exo analysis methods either treat all binding events as being of a uniform type or rely on motifs to cluster binding events into subtypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>To systematically detect multiple protein\u2013DNA interaction modes in a single ChIP-exo experiment, we introduce the ChIP-exo mixture model (ChExMix). ChExMix probabilistically models the genomic locations and subtype memberships of binding events using both ChIP-exo tag distribution patterns and DNA motifs. We demonstrate that ChExMix achieves accurate detection and classification of binding event subtypes using in silico mixed ChIP-exo data. We further demonstrate the unique analysis abilities of ChExMix using a collection of ChIP-exo experiments that profile the binding of key transcription factors in MCF-7 cells. In these data, ChExMix identifies possible recruitment mechanisms of FoxA1 and ER\u03b1, thus demonstrating that ChExMix can effectively stratify ChIP-exo binding events into biologically meaningful subtypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>ChExMix is available from https:\/\/github.com\/seqcode\/chexmix.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Supplementary information<\/jats:title>\n                    <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/bty703","type":"journal-article","created":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T15:31:23Z","timestamp":1535038283000},"page":"903-913","source":"Crossref","is-referenced-by-count":30,"title":["Characterizing protein\u2013DNA binding event subtypes in ChIP-exo data"],"prefix":"10.1093","volume":"35","author":[{"given":"Naomi","family":"Yamada","sequence":"first","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, PA, USA"}]},{"given":"William K M","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, PA, USA"}]},{"given":"Nina","family":"Farrell","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, PA, USA"}]},{"given":"B Franklin","family":"Pugh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, PA, USA"}]},{"given":"Shaun","family":"Mahony","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, PA, USA"}]}],"member":"286","published-online":{"date-parts":[[2018,8,28]]},"reference":[{"key":"2023020108345765800_bty703-B1","first-page":"28","article-title":"Fitting a mixture model by expectation maximization to discover motifs in bipolymers","volume":"2","author":"Bailey","year":"1994","journal-title":"Proc. Int. Conf. Intell. Syst. Mol. Biol"},{"key":"2023020108345765800_bty703-B2","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":"2023020108345765800_bty703-B3","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1093\/bioinformatics\/btt470","article-title":"Identification of transcription factor binding sites from ChIP-seq data at high resolution","volume":"29","author":"Bardet","year":"2013","journal-title":"Bioinformatics"},{"key":"2023020108345765800_bty703-B4","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.cell.2007.05.009","article-title":"High-resolution profiling of histone methylations in the human genome","volume":"129","author":"Barski","year":"2007","journal-title":"Cell"},{"key":"2023020108345765800_bty703-B5","doi-asserted-by":"crossref","first-page":"349.","DOI":"10.1186\/s12859-015-0787-6","article-title":"Peak shape clustering reveals biological insights","volume":"16","author":"Cremona","year":"2015","journal-title":"BMC Bioinformatics"},{"key":"2023020108345765800_bty703-B6","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1126\/science.1136800","article-title":"Clustering by passing messages between data points","volume":"315","author":"Dueck","year":"2007","journal-title":"Science"},{"key":"2023020108345765800_bty703-B7","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1109\/34.990138","article-title":"Unsupervised learning of finite mixture models","volume":"24","author":"Figueiredo","year":"2002","journal-title":"IEEE Trans. Pattern Anal. Mach. Intell"},{"key":"2023020108345765800_bty703-B8","doi-asserted-by":"crossref","first-page":"10588","DOI":"10.1093\/nar\/gkw785","article-title":"CTCF modulates Estrogen Receptor function through specific chromatin and nuclear matrix interactions","volume":"44","author":"Fiorito","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023020108345765800_bty703-B9","author":"Gheorghe","year":"2018"},{"key":"2023020108345765800_bty703-B10","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":"2023020108345765800_bty703-B11","doi-asserted-by":"crossref","first-page":"3028","DOI":"10.1093\/bioinformatics\/btq590","article-title":"Discovering homotypic binding events at high spatial resolution","volume":"26","author":"Guo","year":"2010","journal-title":"Bioinformatics"},{"key":"2023020108345765800_bty703-B12","doi-asserted-by":"crossref","first-page":"e1002638","DOI":"10.1371\/journal.pcbi.1002638","article-title":"High resolution genome wide binding event finding and motif discovery reveals transcription factor spatial binding constraints","volume":"8","author":"Guo","year":"2012","journal-title":"PLoS Comput. Biol"},{"key":"2023020108345765800_bty703-B13","doi-asserted-by":"crossref","first-page":"873.","DOI":"10.1186\/s12864-016-3164-6","article-title":"Q-nexus: a comprehensive and efficient analysis pipeline designed for ChIP-nexus","volume":"17","author":"Hansen","year":"2016","journal-title":"BMC Genomics"},{"key":"2023020108345765800_bty703-B14","doi-asserted-by":"crossref","first-page":"i629","DOI":"10.1093\/bioinformatics\/btw448","article-title":"PeakXus: comprehensive transcription factor binding site discovery from ChIP-Nexus and ChIP-Exo experiments","volume":"32","author":"Hartonen","year":"2016","journal-title":"Bioinformatics"},{"key":"2023020108345765800_bty703-B15","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/nbt.3121","article-title":"ChIP-nexus enables improved detection of in vivo transcription factor binding footprints","volume":"33","author":"He","year":"2015","journal-title":"Nat. Biotechnol"},{"key":"2023020108345765800_bty703-B16","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/ng.730","article-title":"FOXA1 is a key determinant of estrogen receptor function and endocrine response","volume":"43","author":"Hurtado","year":"2011","journal-title":"Nat. Genet"},{"key":"2023020108345765800_bty703-B17","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.molcel.2016.03.001","article-title":"The pioneer transcription factor FoxA maintains an accessible nucleosome configuration at enhancers for tissue-specific gene activation","volume":"62","author":"Iwafuchi-Doi","year":"2016","journal-title":"Mol. Cell"},{"key":"2023020108345765800_bty703-B18","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1126\/science.1141319","article-title":"Genome-wide mapping of in vivo protein\u2013DNA interactions","volume":"316","author":"Johnson","year":"2007","journal-title":"Science"},{"key":"2023020108345765800_bty703-B19","doi-asserted-by":"crossref","first-page":"e119.","DOI":"10.1093\/nar\/gkv577","article-title":"Varying levels of complexity in transcription factor binding motifs","volume":"43","author":"Keilwagen","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2023020108345765800_bty703-B20","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/nbt.2596","article-title":"Uniform, optimal signal processing of mapped deep-sequencing data","volume":"31","author":"Kumar","year":"2013","journal-title":"Nat. Biotechnol"},{"key":"2023020108345765800_bty703-B21","doi-asserted-by":"crossref","first-page":"R25.","DOI":"10.1186\/gb-2009-10-3-r25","article-title":"Ultrafast and memory-efficient alignment of short DNA sequences to the human genome","volume":"10","author":"Langmead","year":"2009","journal-title":"Genome Biol"},{"key":"2023020108345765800_bty703-B22","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence alignment\/map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2023020108345765800_bty703-B23","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2023020108345765800_bty703-B24","doi-asserted-by":"crossref","first-page":"199.","DOI":"10.1186\/1471-2105-13-199","article-title":"Normalization of ChIP-seq data with control","volume":"13","author":"Liang","year":"2012","journal-title":"BMC Bioinformatics"},{"key":"2023020108345765800_bty703-B25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.14806\/ej.21.0.837","article-title":"CexoR: an R package to uncover high-resolution protein\u2013DNA interactions in ChIP-exo replicates","volume":"21","author":"Madrigal","year":"2015","journal-title":"EMBnet.journal"},{"key":"2023020108345765800_bty703-B26","doi-asserted-by":"crossref","first-page":"e1003501.,","DOI":"10.1371\/journal.pcbi.1003501","article-title":"An integrated model of multiple-condition ChIP-Seq data reveals predeterminants of Cdx2 binding","volume":"10","author":"Mahony","year":"2014","journal-title":"PLoS Comput. Biol"},{"key":"2023020108345765800_bty703-B27","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/978-94-011-5014-9_12","volume-title":"Learning in Graphical Models","author":"Neal","year":"1998"},{"key":"2023020108345765800_bty703-B28","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":"2023020108345765800_bty703-B29","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1016\/j.cell.2011.11.013","article-title":"Comprehensive genome-wide protein\u2013DNA interactions detected at single-nucleotide resolution","volume":"147","author":"Rhee","year":"2011","journal-title":"Cell"},{"key":"2023020108345765800_bty703-B30","doi-asserted-by":"crossref","first-page":"R147","DOI":"10.1186\/gb-2013-14-12-r147","article-title":"Development of an Illumina-based ChIP-exonuclease method provides insight into FoxA1-DNA binding properties","volume":"14","author":"Serandour","year":"2013","journal-title":"Genome Biol"},{"key":"2023020108345765800_bty703-B31","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1101\/gr.185157.114","article-title":"ChIP-exo signal associated with DNA-binding motifs provide insights into the genomic binding of the glucocorticoid receptor and cooperating transcription factors","volume":"25","author":"Starick","year":"2015","journal-title":"Genome Res"},{"key":"2023020108345765800_bty703-B32","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1101\/gr.139105.112","article-title":"Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors","volume":"22","author":"Wang","year":"2012","journal-title":"Genome Res"},{"key":"2023020108345765800_bty703-B33","doi-asserted-by":"crossref","first-page":"e156.","DOI":"10.1093\/nar\/gku846","article-title":"MACE: model based analysis of ChIP-exo","volume":"42","author":"Wang","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2023020108345765800_bty703-B34","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1016\/j.cell.2014.08.009","article-title":"Determination and inference of eukaryotic transcription factor sequence specificity","volume":"158","author":"Weirauch","year":"2014","journal-title":"Cell"},{"key":"2023020108345765800_bty703-B35","doi-asserted-by":"crossref","first-page":"e98.","DOI":"10.1093\/nar\/gkr341","article-title":"Inferring transcription factor complexes from ChIP-seq data","volume":"39","author":"Whitington","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"2023020108345765800_bty703-B36","doi-asserted-by":"crossref","first-page":"7540","DOI":"10.1093\/nar\/gkw659","article-title":"Genome-wide analysis reveals positional-nucleosome-oriented binding pattern of pioneer factor FOXA1","volume":"44","author":"Ye","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023020108345765800_bty703-B37","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"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/6\/903\/48967505\/bioinformatics_35_6_903.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/6\/903\/48967505\/bioinformatics_35_6_903.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T14:40:24Z","timestamp":1675262424000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/35\/6\/903\/5085369"}},"subtitle":[],"editor":[{"given":"Inanc","family":"Birol","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2018,8,28]]},"references-count":37,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2019,3,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/bty703","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/266536","asserted-by":"object"}]},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,3,15]]},"published":{"date-parts":[[2018,8,28]]}}}