Inferring Transcription Factor Targets from Gene Expression Changes and Predicted Promoter Occupancy

Abstract

We have developed a method for inferring condition-specific targets of transcription factors based on ranking genes by gene expression change and ranking genes based on predicted transcription factor occupancy. The average of these two ranks, used as a test statistic, allows target genes to be inferred in a stringent manner. The method complements chromatin immunoprecipitation experiments by predicting targets under many conditions for which ChIP experiments have not been performed. We used the method to predict targets of 102 yeast transcription factors in ∼1600 expression microarray experiments. The reliability of the method is suggested by the strong enrichment of genes previously shown to be bound, by the validation of binding to novel targets, by the way transcription factors with similar specificities can be functionally distinguished, and by the greater-than-expected number of regulatory network motifs, such as auto-regulatory interactions, that arise from new, predicted interactions. The combination of ChIP data and the targets inferred from this analysis results in a high-confidence regulatory network that includes many novel interactions. Interestingly, we find only a weak association between conditions in which we can infer the activity of a transcription factor and conditions in which the transcription gene itself is regulated. Thus, methods that rely on transcription factor regulation to help define regulatory interactions may miss regulatory relationships that are detected by the method reported here.