NetREX: Network Rewiring using EXpression - Towards Context Specific Regulatory Networks

Abstract: Understanding gene regulation is a fundamental step towards understanding of how cells function and respond to environmental cues and perturbations. An important step in this direction is to infer the transcription factor-gene regulatory network (GRN). However gene regulatory networks are typically constructed disregarding the fact that regulatory programs are conditioned on tissue type, developmental stage, sex, and other factors. Collecting multitude of features required for a reliable construction of GRNs such as physical features and functional features for every context of interest is costly. Therefore we need methods that is able to use the knowledge of a context-agnostic network for construction of a context specific regulatory network. To address this challenge we developed a computational approach that uses context specific expression data and a GRN constructed in a different but related context to construct a context specific GRN. Our method, NetREX, is inspired by network component analysis that estimates TF activities and their influences on target genes given predetermined topology of a TF-gene network. To predict a network under a different condition, NetREX removes the restriction that the topology of the TF-gene network is fixed and allows for adding and removing edges to that network. To solve the corresponding optimization problem, we provide a general mathematical framework allowing use of the recently proposed PALM technique and develop a convergent algorithm. We tested our NetREX on simulated data and subsequently applied it to gene expression data in adult females from Drosophila deletion (DrosDel) panel. The networks predicted by NetREX showed higher biological consistency than alternative approaches. In addition, we used the list of recently identified targets of the Doublesex (DSX) transcription factor to demonstrate the predictive power of our method.