From expression footprints to causal pathways: contextualizing large signaling networks with CARNIVAL
Anika Liu1,2, Panuwat Trairatphisan1, Enio Gjerga1,2
1Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute of Computational Biomedicine, Bioquant, 69120 Heidelberg, Germany.
NPJ Systems Biology and Applications
|November 16, 2019
Summary
CARNIVAL is a new tool that identifies upstream causes of gene expression changes. It accurately reveals cellular processes and disease-related pathways, like Wnt and TGF-β in IgA nephropathy.
Area of Science:
- Systems Biology
- Bioinformatics
- Genomics
Background:
- Gene expression profiling offers insights into cellular processes but struggles to identify upstream drivers.
- Identifying regulatory networks that cause observed gene expression changes is a significant challenge in molecular biology.
Purpose of the Study:
- To introduce CARNIVAL, a novel computational tool for causal network contextualization.
- To derive network architectures from gene expression data and identify upstream regulatory processes.
Main Methods:
- CARNIVAL integrates prior knowledge (protein-protein interactions, transcription factor targets, pathways) with gene expression data.
- It formulates network identification as an integer linear programming (ILP) problem for efficient computation.
- The tool contextualizes signaling networks by inferring upstream regulators.
Main Results:
- CARNIVAL demonstrates higher accuracy compared to existing tools by leveraging prior biological knowledge.
- Application to IgA nephropathy (IgAN) data identified dysregulated Wnt and TGF-β signaling pathways.
- Experimental validation confirmed the identified pathways and mediators in IgAN.
Conclusions:
- CARNIVAL effectively generates hypotheses about upstream alterations driving signaling networks.
- The tool provides valuable insights into disease mechanisms by uncovering dysregulated pathways.
- CARNIVAL enhances the understanding of complex biological systems and disease pathogenesis.
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