Inferring protein modulation from gene expression data using conditional mutual information

Abstract

Systematic, high-throughput dissection of causal post-translational regulatory dependencies, on a genome wide basis, is still one of the great challenges of biology. Due to its complexity, however, only a handful of computational algorithms have been developed for this task. Here we present CINDy (Conditional Inference of Network Dynamics), a novel algorithm for the genome-wide, context specific inference of regulatory dependencies between signaling protein and transcription factor activity, from gene expression data. The algorithm uses a novel adaptive partitioning methodology to accurately estimate the full Condition Mutual Information (CMI) between a transcription factor and its targets, given the expression of a signaling protein. We show that CMI analysis is optimally suited to dissecting post-translational dependencies. Indeed, when tested against a gold standard dataset of experimentally validated protein-protein interactions in signal transduction networks, CINDy significantly outperforms previous methods, both in terms of sensitivity and precision.