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Computational Biology

Nature Biotechnology 24, 963–970 (1 August 2006) | doi:10.1038/nbt1233

High-resolution computational models of genome binding events

Yuan Qi , Alex Rolfe , Kenzie D MacIsaac , Georg K Gerber , Dmitry Pokholok , Julia Zeitlinger , Timothy Danford , Robin D Dowell , Ernest Fraenkel , Tommi S Jaakkola , Richard A Young & David K Gifford

Direct physical information that describes where transcription factors, nucleosomes, modified histones, RNA polymerase II and other key proteins interact with the genome provides an invaluable mechanistic foundation for understanding complex programs of gene regulation. We present a method, joint binding deconvolution (JBD), which uses additional easily obtainable experimental data about chromatin immunoprecipitation (ChIP) to improve the spatial resolution of the transcription factor binding locations inferred from ChIP followed by DNA microarray hybridization (ChIP-Chip) data. Based on this probabilistic model of binding data, we further pursue improved spatial resolution by using sequence information. We produce positional priors that link ChIP-Chip data to sequence data by guiding motif discovery to inferred protein-DNA binding sites. We present results on the yeast transcription factors Gcn4 and Mig2 to demonstrate JBD's spatial resolution capabilities and show that positional priors allow computational discovery of the Mig2 motif when a standard approach fails.