Optimizing data integration improves gene regulatory network inference in Arabidopsis thaliana.

Abstract

Gene regulatory networks (GRNs) are traditionally inferred from gene expression profiles monitoring a specific condition or treatment. In the last decade, integrative strategies have successfully emerged to guide GRN inference from gene expression with complementary prior data. However, datasets used as prior information and validation gold standards are often related and limited to a subset of genes. This lack of complete and independent evaluation calls for new criteria to robustly estimate the optimal intensity of prior data integration in the inference process. We address this issue for two regression-based GRN inference models, a weighted random forest (weigthedRF) and a generalized linear model estimated under a weighted LASSO penalty with stability selection (weightedLASSO). These approaches are applied to data from the root response to nitrate induction in Arabidopsis thaliana. For each gene, we measure how the integration of transcription factor binding motifs influences model prediction. We propose a new approach, DIOgene, that uses model prediction error and a simulated null hypothesis in order to optimize data integration strength in a hypothesis-driven, gene-specific manner. This integration scheme reveals a strong diversity of optimal integration intensities between genes, and offers good performance in minimizing prediction error as well as retrieving experimental interactions. Experimental results show that DIOgene compares favorably against state-of-the-art approaches and allows to recover master regulators of nitrate induction. The R code and notebooks demonstrating the use of the proposed approaches are available in the repository https://github.com/OceaneCsn/integrative_GRN_N_induction.