Identifying transcription factors and microRNAs as key regulators of pathways using Bayesian inference on known pathway structures

Background: Transcription factors and microRNAs act in concert to regulate gene expression in eukaryotes. Numerous computational methods based on sequence information are available for the prediction of target genes of transcription factors and microRNAs. Although these methods provide a static snapshot of how genes may be regulated, they are not effective for the identification of condition-specific regulators. Results: We propose a new method that combines: a) transcription factors and microRNAs that are predicted to target genes in pathways, with b) microarray expression profiles of microRNAs and mRNAs, in conjunction with c) the known structure of molecular pathways. These elements are integrated into a Bayesian network derived from each pathway that, through probability inference, allows for the prediction of the key regulators in the pathway. We demonstrate 1) the steps to discretize the expression data for the computation of conditional probabilities in a Bayesian network, 2) the procedure to construct a Bayesian network using the structure of a known pathway and the transcription factors and microRNAs predicted to target genes in that pathway, and 3) the inference results as potential regulators of three signaling pathways using microarray expression profiles of microRNA and mRNA in estrogen receptor positive and estrogen receptor negative tumors. Conclusions: We displayed the ability of our framework to integrate multiple sets of microRNA and mRNA expression data, from two phenotypes, with curated molecular pathway structures by creating Bayesian networks. Moreover, by performing inference on the network using known evidence, e.g., status of differentially expressed genes, or by entering hypotheses to be tested, we obtain a list of potential regulators of the pathways. This, in turn, will help increase our understanding about the regulatory mechanisms relevant to the two phenotypes.