bayesian analysis of high-throughput quantitative measurement of protein-dna interactions贝叶斯分析的高通量定量测定protein-dna交互.pdfVIP

Bayesian Analysis of High-Throughput Quantitative Measurement of Protein-DNA Interactions 1 1 1 1 1,2 David D. Pollock *, A. P. Jason de Koning , Hyunmin Kim , Todd A. Castoe , Mair E. A. Churchill , Katerina J. Kechris3 1 Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, United States of America, 2 Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado, United States of America, 3 Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, United States of America Abstract Transcriptional regulation depends upon the binding of transcription factor (TF) proteins to DNA in a sequence-dependent manner. Although many experimental methods address the interaction between DNA and proteins, they generally do not comprehensively and accurately assess the full binding repertoire (the complete set of sequences that might be bound with at least moderate strength). Here, we develop and evaluate through simulation an experimental approach that allows simultaneous high-throughput quantitative analysis of TF binding affinity to thousands of potential DNA ligands. Tens of thousands of putative binding targets can be mixed with a TF, and both the pre-bound and bound target pools sequenced. A hierarchical Bayesian Markov chain Monte Carlo approach determines posterior estimates for the dissociation constants, sequence-specific binding energies, and free TF concentrations. A unique feature of our approach is that dissociation constants are jointly estimated from their inferred degree of binding and from a model of binding energetics, dep