NetREX-CF integrates incomplete transcription factor data with gene expression to reconstruct gene regulatory networks

NetREX-CF is a computational method that integrates collaborative filtering and a mathematical model of transcriptional regulation to predict gene regulatory networks from incomplete transcription factor (TF) binding data and context-specific gene expression. NetREX-CF is used to obtain a comprehensive regulatory network and benchmark resource for Drosophila Schneider 2 cells. The inference of Gene Regulatory Networks (GRNs) is one of the key challenges in systems biology. Leading algorithms utilize, in addition to gene expression, prior knowledge such as Transcription Factor (TF) DNA binding motifs or results of TF binding experiments. However, such prior knowledge is typically incomplete, therefore, integrating it with gene expression to infer GRNs remains difficult. To address this challenge, we introduce NetREX-CF-Regulatory Network Reconstruction using EXpression and Collaborative Filtering-a GRN reconstruction approach that brings together Collaborative Filtering to address the incompleteness of the prior knowledge and a biologically justified model of gene expression (sparse Network Component Analysis based model). We validated the NetREX-CF using Yeast data and then used it to construct the GRN for Drosophila Schneider 2 (S2) cells. To corroborate the GRN, we performed a large-scale RNA-Seq analysis followed by a high-throughput RNAi treatment against all 465 expressed TFs in the cell line. Our knockdown result has not only extensively validated the GRN we built, but also provides a benchmark that our community can use for evaluating GRNs. Finally, we demonstrate that NetREX-CF can infer GRNs using single-cell RNA-Seq, and outperforms other methods, by using previously published human data.

Automated summary

NetREX-CF is a computational method that integrates collaborative filtering and a mathematical model of transcriptional regulation to predict gene regulatory networks. By integrating TF binding data and context-specific gene expression, NetREX-CF can obtain a comprehensive regulatory network for Drosophila Schneider 2 cells. This method is important for inferring gene regulatory networks.