DeepSNEM: Deep Signaling Network Embeddings for compound mechanism of action identification

MotivationThe analysis and comparison of compounds transcriptomic signatures can help elucidate a compounds Mechanism of Action (MoA) in a biological system. In order to take into account the complexity of the biological system, several computational methods have been developed that utilize prior knowledge of molecular interactions to create a signaling network representation that best explains the compounds effect. However, due to their complex structure, large scale datasets of compound-induced signaling networks and methods specifically tailored to their analysis and comparison are very limited. Our goal is to develop graph deep learning models that are optimized to transform compound-induced signaling networks into high-dimensional representations and investigate their relationship with their respective MoAs. ResultsWe created a new dataset of compound-induced signaling networks by applying the CARNIVAL network creation pipeline on the gene expression profiles of the CMap dataset. Furthermore, we developed a novel unsupervised graph deep learning pipeline, called deepSNEM, to encode the information in the compound-induced signaling networks in fixed-length high-dimensional representations. The core of deepSNEM is a graph transformer network, trained to maximize the mutual information between whole-graph and sub-graph representations that belong to similar perturbations. By clustering the deepSNEM embeddings, using the k-means algorithm, we were able to identify distinct clusters that are significantly enriched for mTOR, topoisomerase, HDAC and protein synthesis inhibitors respectively. Additionally, we developed a subgraph importance pipeline and identified important nodes and subgraphs that were found to be directly related to the most prevalent MoA of the assigned cluster. As a use case, deepSNEM was applied on compounds gene expression profiles from various experimental platforms (MicroArrays and RNA sequencing) and the results indicate that correct hypotheses can be generated regarding their MoA. Availability and ImplementationThe source code and pre-trained deepSNEM models are available at https://github.com/BioSysLab/deepSNEM. ContactEmail for correspondence: leo@mail.ntua.gr. Supplementary informationAccompanying supplementary material are available online.