title: Combining transcription factor binding affinities with open-chromatin data for accurate gene expression prediction.
abstract: The binding and contribution of transcription factors (TF) to cell specific gene expression is often deduced from open-chromatin measurements to avoid costly TF ChIP-seq assays. Thus, it is important to develop computational methods for accurate TF binding prediction in open-chromatin regions (OCRs). Here, we report a novel segmentation-based method, TEPIC, to predict TF binding by combining sets of OCRs with position weight matrices. TEPIC can be applied to various open-chromatin data, e.g. DNaseI-seq and NOMe-seq. Additionally, Histone-Marks (HMs) can be used to identify candidate TF binding sites. TEPIC computes TF affinities and uses open-chromatin/HM signal intensity as quantitative measures of TF binding strength. Using machine learning, we find low affinity binding sites to improve our ability to explain gene expression variability compared to the standard presence/absence classification of binding sites. Further, we show that both footprints and peaks capture essential TF binding events and lead to a good prediction performance. In our application, gene-based scores computed by TEPIC with one open-chromatin assay nearly reach the quality of several TF ChIP-seq data sets. Finally, these scores correctly predict known transcriptional regulators as illustrated by the application to novel DNaseI-seq and NOMe-seq data for primary human hepatocytes and CD4+ T-cells, respectively.
authors.affiliation: Cluster of Excellence for Multimodal Computing and Interaction, Saarland Informatics Campus, Saarland University, Saarbrücken, 66123, Germany.|Computational Biology & Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, 66123, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Schmidt
authors.affiliation: Department of Genetics, University of Saarland, Saarbrücken, 66123, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Gasparoni
authors.affiliation: Department of Genetics, University of Saarland, Saarbrücken, 66123, Germany.
authors.forename: Gilles
authors.initials: G
authors.lastname: Gasparoni
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors IfADo, Dortmund, 44139, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Gianmoena
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors IfADo, Dortmund, 44139, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cadenas
authors.affiliation: Experimental Rheumatology, German Rheumatism Research Centre, Berlin, 10117, Germany.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Polansky
authors.affiliation: Computational Biology & Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, 66123, Germany.|International Max Planck Research School for Computer Science, Saarland Informatics Campus, Saarbrücken, 66123, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Ebert
authors.affiliation: Department of Genetics, University of Saarland, Saarbrücken, 66123, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Nordström
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, 24105, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Barann
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, 24105, Germany.
authors.forename: Anupam
authors.initials: A
authors.lastname: Sinha
authors.affiliation: Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin, 13092, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fröhler
authors.affiliation: Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin, 13092, Germany.
authors.forename: Jieyi
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Cluster of Excellence for Multimodal Computing and Interaction, Saarland Informatics Campus, Saarland University, Saarbrücken, 66123, Germany.|Computational Biology & Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, 66123, Germany.|International Max Planck Research School for Computer Science, Saarland Informatics Campus, Saarbrücken, 66123, Germany.
authors.forename: Azim
authors.initials: A
authors.lastname: Dehghani Amirabad
authors.affiliation: Cluster of Excellence for Multimodal Computing and Interaction, Saarland Informatics Campus, Saarland University, Saarbrücken, 66123, Germany.|Computational Biology & Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, 66123, Germany.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Behjati Ardakani
authors.affiliation: Applied Bioinformatics, Deutsches Krebsforschungszentrum, Heidelberg, 69120, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hutter
authors.affiliation: Data Management and Genomics IT, Deutsches Krebsforschungszentrum, Heidelberg, 69120, Germany.
authors.forename: Gideon
authors.initials: G
authors.lastname: Zipprich
authors.affiliation: Data Management and Genomics IT, Deutsches Krebsforschungszentrum, Heidelberg, 69120, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Felder
authors.affiliation: Data Management and Genomics IT, Deutsches Krebsforschungszentrum, Heidelberg, 69120, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eils
authors.affiliation: Applied Bioinformatics, Deutsches Krebsforschungszentrum, Heidelberg, 69120, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin, 13092, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors IfADo, Dortmund, 44139, Germany.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.affiliation: International Max Planck Research School for Computer Science, Saarland Informatics Campus, Saarbrücken, 66123, Germany.
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
authors.affiliation: Computational Biology & Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, 66123, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, 24105, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: Department of Genetics, University of Saarland, Saarbrücken, 66123, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Walter
authors.affiliation: Cluster of Excellence for Multimodal Computing and Interaction, Saarland Informatics Campus, Saarland University, Saarbrücken, 66123, Germany mschulz@mmci.uni-saarland.de.|Computational Biology & Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, 66123, Germany.
authors.forename: Marcel H
authors.initials: MH
authors.lastname: Schulz
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D000069550:Machine Learning; D009928:Organ Specificity; D061251:Primary Cell Culture; D025341:Principal Component Analysis; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D014157:Transcription Factors; D004247:DNA