Illuminating Dark Proteins Using Reactome Pathways.

Timothy Brunson,Nasim Sanati,Lisa Matthews,Robin Haw,Deidre Beavers,Solomon Shorser,Cristoffer Sevilla,Guilherme Viteri,Patrick Conley,Karen Rothfels,Henning HermjakobTop Scholar,Lincoln SteinTop Scholar,Peter D'Eustachio,Guanming Wu

bioRxiv the preprint server for biology（2023）

Oregon Health & Science University | NYU Langone Health | Ontario Institute for Cancer Research

Cited 2|Views13

Abstract

Limited knowledge about a substantial portion of protein coding genes, known as "dark" proteins, hinders our understanding of their functions and potential therapeutic applications. To address this, we leveraged Reactome, the most comprehensive, open source, open-access pathway knowledgebase, to contextualize dark proteins within biological pathways. By integrating multiple resources and employing a random forest classifier trained on 106 protein/gene pairwise features, we predicted functional interactions between dark proteins and Reactome-annotated proteins. We then developed three scores to measure the interactions between dark proteins and Reactome pathways, utilizing enrichment analysis and fuzzy logic simulations. Correlation analysis of these scores with an independent single-cell RNA sequencing dataset provided supporting evidence for this approach. Furthermore, systematic natural language processing (NLP) analysis of over 22 million PubMed abstracts and manual checking of the literature associated with 20 randomly selected dark proteins reinforced the predicted interactions between proteins and pathways. To enhance the visualization and exploration of dark proteins within Reactome pathways, we developed the Reactome IDG portal, deployed at https://idg.reactome.org, a web application featuring tissue-specific protein and gene expression overlay, as well as drug interactions. Our integrated computational approach, together with the user-friendly web platform, offers a valuable resource for uncovering potential biological functions and therapeutic implications of dark proteins.

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Key words

Protein-Protein Interaction Networks,Human Protein Interactome,Pathway Analysis,Transcriptomics,Phenotypic Profiling

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