title: Quantitative modeling of gene expression using DNA shape features of binding sites.
abstract: Prediction of gene expression levels driven by regulatory sequences is pivotal in genomic biology. A major focus in transcriptional regulation is sequence-to-expression modeling, which interprets the enhancer sequence based on transcription factor concentrations and DNA binding specificities and predicts precise gene expression levels in varying cellular contexts. Such models largely rely on the position weight matrix (PWM) model for DNA binding, and the effect of alternative models based on DNA shape remains unexplored. Here, we propose a statistical thermodynamics model of gene expression using DNA shape features of binding sites. We used rigorous methods to evaluate the fits of expression readouts of 37 enhancers regulating spatial gene expression patterns in Drosophila embryo, and show that DNA shape-based models perform arguably better than PWM-based models. We also observed DNA shape captures information complimentary to the PWM, in a way that is useful for expression modeling. Furthermore, we tested if combining shape and PWM-based features provides better predictions than using either binding model alone. Our work demonstrates that the increasingly popular DNA-binding models based on local DNA shape can be useful in sequence-to-expression modeling. It also provides a framework for future studies to predict gene expression better than with PWM models alone.
authors.affiliation: Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Pei-Chen
authors.initials: PC
authors.lastname: Peng
authors.affiliation: Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA sinhas@illinois.edu.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Sinha
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019295:Computational Biology; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D056510:Position-Specific Scoring Matrices; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D013816:Thermodynamics
chemical_list: D004268:DNA-Binding Proteins; D004247:DNA