The Signaling Pathways Project: an integrated ‘omics knowledgebase for mammalian cellular signaling pathways

Public transcriptomic and ChIP-Seq datasets have the potential to illuminate facets of transcriptional regulation by mammalian cellular signaling pathways not yet explored in the research literature. Unfortunately, a variety of obstacles prevent routine re-use of these datasets by bench biologists for hypothesis generation and data validation. Here, we designed a web knowledgebase, the Signaling Pathways Project (SPP), which incorporates stable community classifications of three major categories of cellular signaling pathway node (receptors, enzymes and transcription factors) and the bioactive small molecules (BSMs) known to modulate their functions. We then subjected over 10,000 publically archived transcriptomic or ChIP-Seq experiments to a biocuration pipeline that mapped them to their relevant signaling pathway node, BSM or biosample (tissue or cell line of study). To provide for prediction of pathway node-target transcriptional regulatory relationships, we generated consensus ‘omics signatures, or consensomes, based on the significant differential expression or promoter occupancy of genomic targets across all underlying transcriptomic (expression array and RNA-Seq) or ChIP-Seq experiments. To expose the SPP knowledgebase to biology researchers, we designed a web browser interface that accommodates a variety of routine data mining strategies depending upon the requirements of the end user. Individual dataset pages provide for browsing or filtering, and facilitate integration of SPP with the research literature. Results of single gene, Gene Ontology or user-uploaded gene list queries are displayed in an interactive user interface referred to as the Regulation Report, in which evidence for transcriptional regulation of downstream genomic target by cellular signaling pathway nodes is compartmentalized in an intuitive manner. Consensome queries allow users to evaluate evidence for targets most consistently regulated by a given signaling pathway node family, and allow for detailed inspection of the pharmacology underlying node-target regulatory relationships predicted by the consensomes. Consensomes were validated using alignment with literature-based knowledge, gene target-level integration of transcriptomic and ChIP-Seq data points, and in bench experiments that confirmed previously uncharacterized node-gene target regulatory relationships. SPP is freely accessible at https://beta.signalingpathways.org. Availability and Implementation: The Signaling Pathways Project is freely accessible at https://beta.signalingpathways.org. Social media: @sigpathproject