Perturbation-based gene regulatory network inference to unravel oncogenic mechanisms

BioRxiv : the Preprint Server for Biology
Daniel MorganErik L L Sonnhammer

Abstract

The gene regulatory network (GRN) of human cells encodes mechanisms to ensure proper functioning. However, if this GRN is dysregulated, the cell may enter into a disease state such as cancer. Understanding the GRN as a system can therefore help identify novel mechanisms underlying disease, which can lead to new therapies. Reliable inference of GRNs is however still a major challenge in systems biology. To deduce regulatory interactions relevant to cancer, we applied a recent computational inference framework to data from perturbation experiments in squamous carcinoma cell line A431. GRNs were inferred using several methods, and the false discovery rate was controlled by the NestBoot framework. We developed a novel approach to assess the predictiveness of inferred GRNs against validation data, despite the lack of a gold standard. The best GRN was significantly more predictive than the null model, both in crossvalidated benchmarks and for an independent dataset of the same genes under a different perturbation design. It agrees with many known links, in addition to predicting a large number of novel interactions from which a subset was experimentally validated. The inferred GRN captures regulatory interactions central to cancer-re...Continue Reading

Related Concepts

Genes
Cancer Research
GRN
Human Cell Line
Grn protein, mouse
Drug Interactions
Squamous Cell Carcinoma
Gene Regulatory Networks
Frontotemporal Dementia
Malignant Neoplasms

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