{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T20:46:30Z","timestamp":1772570790960,"version":"3.50.1"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"Supplement_1","license":[{"start":{"date-parts":[[2020,7,13]],"date-time":"2020-07-13T00:00:00Z","timestamp":1594598400000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK091183"],"award-info":[{"award-number":["R01 DK091183"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Foundation Leducq","doi-asserted-by":"crossref","award":["16CVD01"],"award-info":[{"award-number":["16CVD01"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003246","name":"NWO","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Netherlands Organization for Scientific Research"},{"DOI":"10.13039\/100019741","name":"Amsterdam Cardiovascular Sciences","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100019741","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000048","name":"ACS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>Genetic variation in regulatory elements can alter transcription factor (TF) binding by mutating a TF binding motif, which in turn may affect the activity of the regulatory elements. However, it is unclear which motifs are prone to impact transcriptional regulation if mutated. Current motif analysis tools either prioritize TFs based on motif enrichment without linking to a function or are limited in their applications due to the assumption of linearity between motifs and their functional effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We present MAGGIE (Motif Alteration Genome-wide to Globally Investigate Elements), a novel method for identifying motifs mediating TF binding and function. By leveraging measurements from diverse genotypes, MAGGIE uses a statistical approach to link mutations of a motif to changes of an epigenomic feature without assuming a linear relationship. We benchmark MAGGIE across various applications using both simulated and biological datasets and demonstrate its improvement in sensitivity and specificity compared with the state-of-the-art motif analysis approaches. We use MAGGIE to gain novel insights into the divergent functions of distinct NF-\u03baB factors in pro-inflammatory macrophages, revealing the association of p65\u2013p50 co-binding with transcriptional activation and the association of p50 binding lacking p65 with transcriptional repression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>The Python package for MAGGIE is freely available at https:\/\/github.com\/zeyang-shen\/maggie. The accession number for the NF-\u03baB ChIP-seq data generated for this study is Gene Expression Omnibus: GSE144070.<\/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\/btaa476","type":"journal-article","created":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T15:19:51Z","timestamp":1588691991000},"page":"i84-i92","source":"Crossref","is-referenced-by-count":20,"title":["MAGGIE: leveraging genetic variation to identify DNA sequence motifs mediating transcription factor binding and function"],"prefix":"10.1093","volume":"36","author":[{"given":"Zeyang","family":"Shen","sequence":"first","affiliation":[{"name":"School of Medicine Department of Cellular and Molecular Medicine,"},{"name":"Jacobs School of Engineering Department of Bioengineering,"}]},{"given":"Marten A","family":"Hoeksema","sequence":"additional","affiliation":[{"name":"School of Medicine Department of Cellular and Molecular Medicine,"}]},{"given":"Zhengyu","family":"Ouyang","sequence":"additional","affiliation":[{"name":"School of Medicine Department of Cellular and Molecular Medicine,"}]},{"given":"Christopher","family":"Benner","sequence":"additional","affiliation":[{"name":"School of Medicine, University of California Department of Medicine, , San Diego, CA 92093, USA"}]},{"given":"Christopher K","family":"Glass","sequence":"additional","affiliation":[{"name":"School of Medicine Department of Cellular and Molecular Medicine,"},{"name":"School of Medicine, University of California Department of Medicine, , San Diego, CA 92093, USA"}]}],"member":"286","published-online":{"date-parts":[[2020,7,13]]},"reference":[{"key":"2024021913364185800_btaa476-B1","doi-asserted-by":"crossref","first-page":"dev137729","DOI":"10.1242\/dev.137729","article-title":"Developing in 3D: the role of CTCF in cell differentiation","volume":"145","author":"Arzate-Mej\u00eda","year":"2018","journal-title":"Development"},{"key":"2024021913364185800_btaa476-B2","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.molcel.2014.04.006","article-title":"Coregulation of transcription factor binding and nucleosome occupancy through DNA features of mammalian enhancers","volume":"54","author":"Barozzi","year":"2014","journal-title":"Mol. Cell"},{"key":"2024021913364185800_btaa476-B3","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fgene.2016.00024","article-title":"Analysis of genomic sequence motifs for deciphering transcription factor binding and transcriptional regulation in eukaryotic cells","volume":"7","author":"Boeva","year":"2016","journal-title":"Front. Genet"},{"key":"2024021913364185800_btaa476-B4","article-title":"Considering abundance, affinity, and binding site availability in the NK-\u03baB target selection puzzle","volume":"10, 609","author":"Brignall","year":"2019","journal-title":"Front. Immunol"},{"key":"2024021913364185800_btaa476-B5","doi-asserted-by":"crossref","first-page":"ra11","DOI":"10.1126\/scisignal.2001501","article-title":"The specificity of innate immune responses is enforced by repression of interferon response elements by NF-\u03baB p50","volume":"4","author":"Cheng","year":"2011","journal-title":"Sci. Signal"},{"key":"2024021913364185800_btaa476-B6","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/nature10808","article-title":"DNase I sensitivity QTLs are a major determinant of human expression variation","volume":"482","author":"Degner","year":"2012","journal-title":"Nature"},{"key":"2024021913364185800_btaa476-B7","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.cell.2016.07.012","article-title":"The genetics of transcription factor DNA binding variation","volume":"166","author":"Deplancke","year":"2016","journal-title":"Cell"},{"key":"2024021913364185800_btaa476-B8","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature13835","article-title":"Genetic and epigenetic fine mapping of causal autoimmune disease variants","volume":"518","author":"Farh","year":"2015","journal-title":"Nature"},{"key":"2024021913364185800_btaa476-B9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-08236-0","article-title":"Diverse motif ensembles specify non-redundant DNA binding activities of AP-1 family members in macrophages","volume":"10","author":"Fonseca","year":"2019","journal-title":"Nat. Commun"},{"key":"2024021913364185800_btaa476-B10","first-page":"D87","article-title":"JASPAR 2020: update of the open-access database of transcription factor binding profiles","volume":"48","author":"Fornes","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"2024021913364185800_btaa476-B11","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/ni.3306","article-title":"Molecular control of activation and priming in macrophages","volume":"17","author":"Glass","year":"2016","journal-title":"Nat. Immunol"},{"key":"2024021913364185800_btaa476-B12","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0092-8674(00)80955-1","article-title":"Transcription factors in lymphocyte development\u2014T and B cells get together","volume":"96","author":"Glimcher","year":"1999","journal-title":"Cell"},{"key":"2024021913364185800_btaa476-B13","doi-asserted-by":"crossref","first-page":"E1291","DOI":"10.1073\/pnas.1621150114","article-title":"Systematic dissection of genomic features determining transcription factor binding and enhancer function","volume":"114","author":"Grossman","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2024021913364185800_btaa476-B14","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1016\/j.cell.2015.07.048","article-title":"Genetic control of chromatin states in humans involves local and distal chromosomal interactions","volume":"162","author":"Grubert","year":"2015","journal-title":"Cell"},{"key":"2024021913364185800_btaa476-B15","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1126\/science.1262110","article-title":"The genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans","volume":"348","year":"2015","journal-title":"Science"},{"key":"2024021913364185800_btaa476-B16","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.molcel.2010.05.004","article-title":"Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities","volume":"38","author":"Heinz","year":"2010","journal-title":"Mol. Cell"},{"key":"2024021913364185800_btaa476-B17","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/nature12615","article-title":"Effect of natural genetic variation on enhancer selection and function","volume":"503","author":"Heinz","year":"2013","journal-title":"Nature"},{"key":"2024021913364185800_btaa476-B18","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/nrm3949","article-title":"The selection and function of cell type-specific enhancers","volume":"16","author":"Heinz","year":"2015","journal-title":"Nat. Rev. Mol. Cell Biol"},{"key":"2024021913364185800_btaa476-B19","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1016\/j.cell.2018.07.047","article-title":"Transcription elongation can affect genome 3D structure","volume":"174","author":"Heinz","year":"2018","journal-title":"Cell"},{"key":"2024021913364185800_btaa476-B20","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1186\/s12859-016-1298-9","article-title":"Evaluating tools for transcription factor binding site prediction","volume":"17","author":"Jayaram","year":"2016","journal-title":"BMC Bioinformatics"},{"key":"2024021913364185800_btaa476-B21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-04406-2","article-title":"Genome-scale identification of transcription factors that mediate an inflammatory network during breast cellular transformation","volume":"9","author":"Ji","year":"2018","journal-title":"Nat. Commun"},{"key":"2024021913364185800_btaa476-B22","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/nrg.2015.17","article-title":"Role of non-coding sequence variants in cancer","volume":"17","author":"Khurana","year":"2016","journal-title":"Nat. Rev. Genet"},{"key":"2024021913364185800_btaa476-B23","doi-asserted-by":"crossref","first-page":"D252","DOI":"10.1093\/nar\/gkx1106","article-title":"HOCOMOCO: towards a complete collection of transcription factor binding models for human and mouse via large-scale ChIP-Seq analysis","volume":"46","author":"Kulakovskiy","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2024021913364185800_btaa476-B24","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nature14248","article-title":"Integrative analysis of 111 reference human epigenomes","volume":"518","author":"Kundaje","year":"2015","journal-title":"Nature"},{"key":"2024021913364185800_btaa476-B25","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.cell.2018.01.029","article-title":"The human transcription factors","volume":"172","author":"Lambert","year":"2018","journal-title":"Cell"},{"key":"2024021913364185800_btaa476-B26","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat. Methods"},{"key":"2024021913364185800_btaa476-B27","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1016\/j.cell.2018.04.018","article-title":"Analysis of genetically diverse macrophages reveals local and domain-wide mechanisms that control transcription factor binding and function","volume":"173","author":"Link","year":"2018","journal-title":"Cell"},{"key":"2024021913364185800_btaa476-B28","doi-asserted-by":"crossref","first-page":"7006","DOI":"10.1093\/nar\/gky491","article-title":"MMARGE: motif mutation analysis for regulatory genomic elements","volume":"46","author":"Link","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2024021913364185800_btaa476-B29","doi-asserted-by":"crossref","first-page":"D896","DOI":"10.1093\/nar\/gkw1133","article-title":"The new NHGRI-EBI catalog of published genome-wide association studies (GWAS catalog)","volume":"45","author":"MacArthur","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2024021913364185800_btaa476-B30","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1093\/bioinformatics\/btr189","article-title":"MEME-ChIP: motif analysis of large DNA datasets","volume":"27","author":"Machanick","year":"2011","journal-title":"Bioinformatics"},{"key":"2024021913364185800_btaa476-B31","doi-asserted-by":"crossref","first-page":"W127","DOI":"10.1093\/nar\/gkz363","article-title":"QBiC-Pred: quantitative predictions of transcription factor binding changes due to sequence variants","volume":"47","author":"Martin","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2024021913364185800_btaa476-B32","doi-asserted-by":"crossref","first-page":"D108","DOI":"10.1093\/nar\/gkj143","article-title":"TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes","volume":"34","author":"Matys","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"2024021913364185800_btaa476-B952453","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1126\/science.1242429","article-title":"Identification of Genetic Variants That Affect Histone Modifications in Human Cells","volume":"342","author":"McVicker","year":"2013","journal-title":"Science"},{"key":"2024021913364185800_btaa476-B33","doi-asserted-by":"crossref","first-page":"dev148296","DOI":"10.1242\/dev.148296","article-title":"RUNX transcription factors: orchestrators of development","volume":"146","author":"Mevel","year":"2019","journal-title":"Development"},{"key":"2024021913364185800_btaa476-B34","doi-asserted-by":"crossref","first-page":"5655","DOI":"10.1038\/onc.2013.565","article-title":"Mechanisms and consequences of constitutive NF-\u03baB activation in B-cell lymphoid malignancies","volume":"33","author":"Nagel","year":"2014","journal-title":"Oncogene"},{"key":"2024021913364185800_btaa476-B35","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/ni1196","article-title":"Interactions of NF-\u03baB with chromatin: the art of being at the right place at the right time","volume":"6","author":"Natoli","year":"2005","journal-title":"Nat. Immunol"},{"key":"2024021913364185800_btaa476-B36","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1214\/11-AOAS466","article-title":"Measuring reproducibility of high-throughput experiments","volume":"5","author":"Li","year":"2011","journal-title":"Ann. Appl. Stat"},{"key":"2024021913364185800_btaa476-B37","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.gde.2016.12.007","article-title":"Combinatorial function of transcription factors and cofactors","volume":"43","author":"Reiter","year":"2017","journal-title":"Curr. Opin. Genet. Dev"},{"key":"2024021913364185800_btaa476-B38","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.molcel.2015.05.004","article-title":"High-throughput sequencing technologies","volume":"58","author":"Reuter","year":"2015","journal-title":"Mol. Cell"},{"key":"2024021913364185800_btaa476-B39","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1126\/science.8079170","article-title":"Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages","volume":"265","author":"Scott","year":"1994","journal-title":"Science"},{"key":"2024021913364185800_btaa476-B40","doi-asserted-by":"crossref","DOI":"10.25080\/Majora-92bf1922-011","article-title":"Statsmodels: econometric and statistical modeling with python","author":"Seabold","year":"2010"},{"key":"2024021913364185800_btaa476-B41","first-page":"10106","article-title":"Evaluating the impact of single nucleotide variants on transcription factor binding","volume":"44","author":"Shi","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2024021913364185800_btaa476-B42","doi-asserted-by":"crossref","first-page":"6055","DOI":"10.1093\/nar\/gkw521","article-title":"Bayesian Markov models consistently outperform PWMs at predicting motifs in nucleotide sequences","volume":"44","author":"Siebert","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2024021913364185800_btaa476-B43","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/nrg3207","article-title":"Transcription factors: from enhancer binding to developmental control","volume":"13","author":"Spitz","year":"2012","journal-title":"Nat. Rev. Genet"},{"key":"2024021913364185800_btaa476-B44","doi-asserted-by":"crossref","first-page":"R49","DOI":"10.1186\/gb-2012-13-9-r49","article-title":"Analysis of variation at transcription factor binding sites in drosophila and humans","volume":"13","author":"Spivakov","year":"2012","journal-title":"Genome Biol"},{"key":"2024021913364185800_btaa476-B45","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":"2024021913364185800_btaa476-B46","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"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/Supplement_1\/i84\/56702659\/bioinformatics_36_supplement1_i84.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/Supplement_1\/i84\/56702659\/bioinformatics_36_supplement1_i84.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T08:47:57Z","timestamp":1708332477000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/36\/Supplement_1\/i84\/5870471"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,1]]},"references-count":47,"journal-issue":{"issue":"Supplement_1","published-print":{"date-parts":[[2020,7,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btaa476","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.01.30.925917","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":[[2020,7]]},"published":{"date-parts":[[2020,7,1]]}}}