title: Building accurate sequence-to-affinity models from high-throughput in vitro protein-DNA binding data using FeatureREDUCE.
abstract: Transcription factors are crucial regulators of gene expression. Accurate quantitative definition of their intrinsic DNA binding preferences is critical to understanding their biological function. High-throughput in vitro technology has recently been used to deeply probe the DNA binding specificity of hundreds of eukaryotic transcription factors, yet algorithms for analyzing such data have not yet fully matured. Here, we present a general framework (FeatureREDUCE) for building sequence-to-affinity models based on a biophysically interpretable and extensible model of protein-DNA interaction that can account for dependencies between nucleotides within the binding interface or multiple modes of binding. When training on protein binding microarray (PBM) data, we use robust regression and modeling of technology-specific biases to infer specificity models of unprecedented accuracy and precision. We provide quantitative validation of our results by comparing to gold-standard data when available.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, United States.|Department of Systems Biology, Columbia University, New York, United States.|Department of Biology, University of Massachusetts Boston, Boston, United States.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Riley
authors.affiliation: Department of Biological Sciences, Columbia University, New York, United States.|Department of Electrical Engineering, Columbia University, New York, United States.
authors.forename: Allan
authors.initials: A
authors.lastname: Lazarovici
authors.affiliation: Department of Systems Biology, Columbia University, New York, United States.|Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Mann
authors.affiliation: Department of Biological Sciences, Columbia University, New York, United States.|Department of Systems Biology, Columbia University, New York, United States.
authors.forename: Harmen J
authors.initials: HJ
authors.lastname: Bussemaker
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D055592:Biophysical Phenomena; D019295:Computational Biology / Q000379:methods*; D004247:DNA / Q000378:metabolism*; D046228:Microarray Analysis; D008962:Models, Theoretical; D011485:Protein Binding; D012984:Software; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D004247:DNA
keywords: DNA binding specificity; biophysical model; computational biology; none; protein binding microarray technology; systems biology; transcription factor