From expression footprints to causal pathways: contextualizing large signaling networks with CARNIVAL

Abstract

While gene expression profiling is commonly used to gain an overview of cellular processes, the identification of upstream processes that drive expression changes remains a challenge. To address this issue, we introduce CARNIVAL, a causal network contextualization tool which derives network architectures from gene expression footprints. CARNIVAL (CAusal Reasoning pipeline for Network identification using Integer VALue programming) integrates different sources of prior knowledge including signed and directed protein–protein interactions, transcription factor targets, and pathway signatures. The use of prior knowledge in CARNIVAL enables capturing a broad set of upstream cellular processes and regulators, leading to a higher accuracy when benchmarked against related tools. Implementation as an integer linear programming (ILP) problem guarantees efficient computation. As a case study, we applied CARNIVAL to contextualize signaling networks from gene expression data in IgA nephropathy (IgAN), a condition that can lead to chronic kidney disease. CARNIVAL identified specific signaling pathways and associated mediators dysregulated in IgAN including Wnt and TGF-β, which we subsequently validated experimentally. These results demonstrated how CARNIVAL generates hypotheses on potential upstream alterations that propagate through signaling networks, providing insights into diseases.

Network inference: causal reasoning from expression and prior knowledge

Changes in gene expression are generally indirect consequences of upstream dysregulation, and it is often important to understand what caused it. A team of researchers led by Julio Saez-Rodriguez from Heidelberg and Aachen has developed CARNIVAL to infer causal networks of proteins upstream of gene expression. In the first step, dysregulated transcription factors are inferred from gene expression. Subsequently, an algorithm finds explanations for their up- or down-regulation through known protein–protein interactions using an ILP formulation. Optionally, known targets of perturbation can be provided. This integration of different sources of prior knowledge led to higher performance than alternative methods and was able to identify key pathways and proteins, including TGFβ signaling and β-Catenin, in a case study on IgA nephropathy. Overall, CARNIVAL may provide clues to understand causal mechanisms in diseases and treatments.